This chapter on gross and microscopic anatomy is based in part of Chapter 3, Histology, by Elizabeth Fekete ( 1941) in the first edition of the Biology of the Laboratory Mouse. We presuppose a general knowledge of mammalian anatomy and histology. We have added observations on the gross anatomy of skeletal, circulatory, and organ systems; on development of organs; and on sex, age, and strain differences in morphology. Except in rare instances, we have not included fine structure nor functional attributes as revealed by electron microscopy and histochemistry.
We have made no comprehensive detailed study of gross anatomy, referring rather to atlases on anatomy of the rat ( Greene, 1955) and of the mouse ( Cook, 1965). Some morphological differences between rat and mouse have been recorded. No descriptions of muscular or nervous systems are included; organs of special sense are described in Chapter 32 and blood and hematopoietic tissues in Chapter 17.
We have adhered to the terminology of comparative vertebrate anatomy rather than that of human anatomy in the following respects: anterior and cephalic for head end, posterior and caudal for tail end, dorsal for the back or vertebral side, and ventral for the under or belly side.
The axial skeleton is composed of skull, vertebral column, sternum, and ribs; the appendicular skeleton of the paired girdles and appendages. In addition, there are 43 sesamoid bones of three general types ( Wirtschafter and Tsujimura, 1961). For a detailed description of the anatomy and growth of the bones of the normal skeleton, see Bateman ( 1954).
This is the main support of the body and also serves to protect the brain within the cranial cavity, the spinal cord within the vertebral column, and the heart and lungs within the thoracic basket formed by the vertebrae, ribs, and sternum.
The skull closely resembles that of the rat but has a relatively wider and more rounded cranium ( Kutuzov and Sicher, 1953). From the dorsal aspect, the following bones can be identified: the unpaired occipital and interparietal; and the paired parietals, frontals, nasals, premaxillae, maxillae, zygomatics, and squamosals ( Figure 13-1). The occipital forms the posterior wall of the cranial cavity, the interparietal a portion of the roof, and the parietals most of the roof and a portion of the sides of the cranial cavity. Frontals and nasals cover the anterior portions of the brain and with premaxillae, maxillae, zygomatics, and squamosals form the face and upper jaw.
The vertebral column (spine) articulates anteriorly with the occipital bone of the skull, forms the middorsal support of the thoracic and abdominal cavities, and constitutes the skeleton of the tail. It is composed of the following groups of vertebrae: seven cervical, the most anterior being the atlas and axis; 12, 13, or 14 thoracic, each articulating with a pair of ribs; five or six lumbar; four sacral, some articulating with the innominate bones of the pelvic girdle; and 27 to 30 caudal. Of the 25 to 27 presacral vertebrae, seven are invariably cervical, but the numbers of thoracic and lumbar vertebrae differ with strain, sex, and environmental factors (Grüneberg 1952, 1963; Green, 1962).
Sternum. The sternum forms the ventral support of the thoracic basket and consists of six connected parts: the manubrium articulating laterally with the paired clavicles and first ribs, four sternebrae articulating with more posterior ribs, and the xiphisternum, which is a slender segment extending posteriorly beyond the rib attachments and terminating in a cartilaginous xiphoid process. Bifurcation of the xiphisternum is not uncommon and is characteristic of short ear ( se/ se) mice ( Green and McNutt, 1941). The sternum is first visible in the 12-day embryo as a mesenchymal condensation on either side of the midventral line in the thorax. Elongation, chondrification, and medial movement of the sternal bands result in a single continuous cartilage bar by the 16th embryonic day, and segmentation and ossification follow, producing the six bony segments present at birth ( Chen, 1952).
Ribs. These are 12, 13, or 14 pairs of slender curved bones, all articulating dorsally with thoracic vertebrae and some ventrally with the sternum, thus forming the thoracic basket. The dorsal segments are ossified and the ventral segments calcified. Usually the ventral segments of the first seven pairs of ribs attach to the sternum, whereas more posterior pairs join the ventral segment of the seventh rib, and the most posterior three or four have no ventral attachments.
This includes the paired pectoral and pelvic girdles and the bones of the limbs. There is considerable variation in size and structural detail of girdles and long bones of limbs in mice of different strains ( Stein, 1957).
Girdles. Each pectoral girdle consists of dorsal scapula and ventral clavicle. The scapula is a flat trapezoid bone resting against the anterior ribs with its base toward the vertebral column and its pointed end articulating laterally with the humerus and clavicle. The clavicle is a slender curved bone articulating ventrally with the manubrium and laterally with the scapula.
The pelvic girdle of the adult consists of right and left innominate bones attached dorsally to one or more sacral vertebrae and joined ventrally at the pubic symphysis. Three separate bones (ilium, ischium, and pubis) fuse to form the innominate bone, although fusion between the ischium and pubis may be delayed or incomplete in mice of certain strains ( Stein, 1957). The pelves of adults exhibit sexual dimorphism. The presence of the testis is necessary for the development of the male type body pelvis, the influence of the male sex hormone becoming irreversible by 21 days of age ( Crelin, 1960). The pelvis of the female is wider and is located farther ventrally and caudally, the pubic symphysis being opposite the second caudal vertebra rather than opposite the first as in the male.
Limbs. The bones of the forelimb are humerus, radius and ulna, eight carpals, five metacarpals, five first phalanges, four second phalanges, and five third phalanges with their tips. The preaxial digit (thumb or pollex) is much shorter than the other four, lacks a middle phalanx, and has a very short distal one. The bones of the hind limb are femur, tibia and fibula, seven tarsals, five metatarsals, and the same number of phalanges as in the forepaw. The first or great toe (hallux) lacks the middle phalanx but is not so short as the pollex. The tibia and fibula are separate for the proximal two-thirds of their length, are fused along the distal third, but again free at the distal extremities. For the articulations of the bones of the hind limb and foot, see Carter ( 1951) and for their development, see Carter ( 1954); for development of fore and hind limbs, see Forsthoefel ( 1959, 1963).
This brief description includes only heart and principal blood vessels. For details, see Greene ( 1955) and Cook ( 1965).
Gross anatomy. The heart lies in the pericardial cavity, a division of the thoracic cavity, and consists of four muscular-walled chambers, the left and right atria and the left and right ventricles ( Figure 13-2). As in other mammals there is no direct communication between left and right sides after birth. Blood from the body is carried in veins to the right atrium, then into the right ventricle, and through the pulmonary artery to the lungs. Oxygenated blood from the lungs enters the left atrium, passes into the left ventricle, and then into the aorta to be distributed to all parts of the body.
Valves at the atrioventricular orifices and at the bases of the large arteries prevent reverse flow of blood. The right atrioventricular orifice is guarded by the tricuspid valve, three leaflets extending into the ventricular cavity and held in place by tendinous cords. These lead from the edges of the leaflets to muscular pillars (papillary muscles) projecting from the wall of the ventricle. A similar, but bicuspid, valve (the mitral) guards of the left atrioventricular orifice. The openings of right and left ventricles into pulmonary artery and aorta respectively are guarded by trios of semilunar valves. These pocketlike extensions of the ventricular lining fill with blood and close the openings during relaxation of the ventricle walls.
Microscopic anatomy. Three main layers can be identified in heart wall: the endocardium, a thin layer lining the cavities and covering the valves; the myocardium, a muscle layer that is thin in the atria and considerably thicker in the left than the right ventricle; and the epicardium, a thin covering layer. The endocardium consists of endothelial cells plus loose connective tissue binding them to the underlying muscle. The valves are folds of endocardium in which the connective tissue is fibrous. In old mice cartilage cells often can be observed within the fibrous tissue at the bases of the valve cusps. The myocardium consists of spiral sheets of cardiac muscle bound together by connective tissue supporting blood vessels and nerves. The epicardium consists of a thin layer of connective tissue and a mesothelial layer or pericardium continuous with the lining of the pericardial cavity surrounding the heart.
Gross anatomy. The principal vessels carrying blood from the heart are the pulmonary artery from the right ventricle and the aorta from the left ventricle ( Figure 13-2). Branches of these arteries supply all parts of the body, their origins and pathways being somewhat variable in individuals as well as in strains ( Froud, 1959).
The pulmonary artery arises from the base of the right ventricle ventral to the base of the left ventricle and aorta. It is a short vessel, soon dividing into right and left branches to the right and left lung lobes.
The aorta arises from the left ventricle dorsal to the pulmonary artery, extends anteriorly (ascends) a short distance, arches to the left, then passes posteriorly (descends) through the thoracic and abdominal cavities and into the tail ( Figure 13-3). The right and left coronary vessels supplying the heart are the only branches from the ascending limb. The innominate, left common carotid, and left subclavian arise from the arch. A short distance from its origin, the innominate divides into right subclavian and right common carotid. The subclavians and their branches supply the pectoral girdles, forelimbs, and thorax, and the carotids supply head and neck.
The thoracic portion of the descending aorta extends from the aortic arch to the diaphragm, lying only slightly left of the vertebral column anteriorly and approaching the midline near the diaphragm. Its main branches supply the thoracic viscera (trachea, bronchi, esophagus, etc.) and the intercostal muscles.
The abdominal portion of the descending aorta extends along the midline of the vertebral column from the diaphragm to the lumbosacral region where it divides into right and left common iliac arteries supplying pelvic and hind limb regions. Visceral branches of the abdominal aorta supply the organs; parietal branches supply the body wall. The first large branch is the celiac trunk, an unpaired artery supplying liver, stomach, spleen, duodenum, and pancreas. The next branch is the superior mesenteric, a large unpaired vessel branching through the mesentery and supplying all of the small intestine, cecum, and ascending and transverse colons. Next are the paired renal arteries to the adrenals and kidneys. These are asymmetrical, the right being more anterior than the left. The right renal may arise anterior to the superior mesenteric and usually is dorsal to the inferior vena cava and to the renal vein and slightly anterior to the latter. The paired genital arteries (spermatic or ovarian) usually arise from the aorta posterior to the renals but their pattern is extremely variable; they may branch from the renals of from the renal aortic junction and they are seldom bilaterally symmetrical. The unpaired inferior mesenteric artery arises from the ventral surface of the aorta close to its division into common iliacs and supplies the descending colon and rectum. The lumbar arteries are segmental pairs arising from the dorsal surface of the aorta and supplying the dorsal musculature. The common iliacs supply the pelvis and hind limbs, and the middle caudal continues the course of the aorta into the tail.
Microscopic anatomy. Three layers, intima, media, and adventitia (externa), can be distinguished in the walls of most arteries. The intima consists of endothelial cells on a connective tissue bed which in large arteries contains a network of elastic fibers. The media is composed of alternating layers of smooth muscle fibers and elastic fibers, the number and relative width of the layers varying in with vessel caliber. In the aorta there are 6 to 10 layers intermingled with fine collagenous fibers; in smaller arteries there are more muscle than elastic fibers; and in arterioles few muscle and no elastic fibers. The adventitia is a layer of loose connective tissue merging with that of surrounding structures.
Capillaries and sinusoids
Extensive networks of capillaries connect terminal arterioles and beginning veins in most organs. The capillary walls are composed of single layers of endothelial cells accompanied by reticular tissue. In some organs irregular spaces or sinusoids connect arteries and veins. The thin walls are formed of irregularly scattered phagocytic and nonphagocytic reticulum cells accompanied by networks of reticular fibers.
Gross anatomy. The principal veins entering the atria of the heart are the pulmonary veins from the lungs; the superior venae cavae from the head, neck, chest, and forelimbs; and the inferior vena cava from regions of the body posterior to the diaphragm ( Figure 13-2).
The left and right pulmonary veins short vessels formed by the union of smaller veins from the lobules and lobes of the lung enter the left atrium of the heart. The right pulmonary vein passes dorsal to the right superior vena cava, the left pulmonary dorsal to the left superior vena cava.
The right and left superior venae cavae, carrying blood from regions of the body anterior to the diaphragm, enter the right atrium. The right vein is short and opens directly into the atrium on its anterior border. The left vein extends farther posteriorly, passes ventral to the pulmonary arteries and veins and dorsal to the base of the ventricles, joins the unpaired inferior vena cava, and enters the right atrium on its posterior border. Each superior vena cava is formed by the confluence of the jugular vein from head and neck and the subclavian vein from forelimb and chest. Coronary veins from the heart join the left superior vena cava and also enter the right atrium directly. The unpaired azygos vein from the intercostal spaces lies to the left of the aorta and vertebral column and joins the left superior vena cava.
The inferior vena cava is an unpaired vessel originating in the union of left and right iliac veins from the pelvic and hind limb regions. It lies to the right of the vertebral column and aorta, is dorsal to the aorta in the lumbar region, and is ventral to it in the renal region. Veins from the dorsal musculature and gonads join it posterior to the large renal veins from the kidneys and adrenals. Like the renal arteries, the renal veins are asymmetrical and vary in position relative to nearby arteries, veins, and organs. The inferior vena cava enters the liver at the base of the posterior subdivision of the right lateral lobe, passes through the liver receiving therein numerous hepatic branches, and emerges from the anterior surface of the median lobe still to the right of the midline. It then pierces the diaphragm, traverses the thoracic cavity, and joins the left superior vena cava where it enters the right atrium.
An important tributary of the inferior vena cava is the hepatic portal vein, formed by the union of veins from the stomach, intestine, pancreas, and spleen. It passes through the mesentery dorsal to the duodenum to enter the median lobe of the liver close to the gall bladder. In the liver, branches of the hepatic portal vein communicate with the liver sinusoids which drain into the hepatic veins and thence into the inferior vena cava. In anomalous conditions, the hepatic portal vessel may pass ventral to the duodenum, enter one of the lateral lobes, and branch before entering the liver.
Microscopic anatomy. Veins are similar to arteries but have thinner, softer, and less elastic walls in which the three layers are frequently indistinct. In small veins the smooth muscle of the media is replaced by connective tissue, and in pulmonary veins by cardiac muscle. The walls of many veins contain paired semilunar valves formed of folds of the intima.
This includes the vessels through which lymph is transported from tissue spaces to the blood circulation, the nodes that lie in the course of the vessels, and the peripheral nodules present at the beginnings of lymph channels in the digestive tube. There are no palatine and no pharyngeal tonsils.
Gross anatomy. Lymph flows from lymph capillaries into successively larger vessels, thence into ducts that empty into veins in the neck. In the rat, lymph vessels unite to form two main ducts one on each side of the vertebral column ( Job, 1915). The small right duct opens into the right superior vena cava at the junction or right jugular and subclavian veins. The thoracic duct is the larger duct on the left that opens into the junction of left subclavian and jugular veins. A pouchlike dilatation, the cisterna chyli, on the dorsal abdominal wall slightly anterior to the kidneys, identifies the beginning of the thoracic duct. In the mouse only certain subsidiary pathways such as that from the tail have been traced ( Engeset and Tjötta, 1960).
Microscopic anatomy. Lymph capillaries are thin-walled vessels with irregular lumina and frequent dilatations and constrictions. Their walls are single layers of endothelial cells. In the larger vessels, collagenous, elastic, and smooth muscle fibers surround the endothelial layer. In still larger vessels, intima, media, and adventitia can be distinguished and folds of the intima form paired valves. The intima consists of endothelium and a layer of elastic fibers, the media of circularly arranged smooth muscle fibers, and the adventitia of longitudinally oriented elastic, collagenous, and smooth muscle fibers.
Gross anatomy. The nodes are bean-shaped structures of varied size located in the course of lymph vessels, interrupting their continuity. Nodes are found in connective tissue subcutaneously, between muscles, and near viscera in body cavities. The number and size of visible nodes varies with individuals and environmental conditions. Strain differences in size have been reported, nodes of C3H mice being larger at all ages than those of mice of other strains ( Albert and Johnson, 1960). The locations ( Figure 13-4) and the names and descriptions of nodes visible under normal conditions are based on the observations of Dunn ( 1954).
All nodes beneath the skin and between muscles are bilateral. The principal ones are two superficial cervicals on the anterior ventral margin of the submandibular gland, one or two very small deep cervicals, buried in the connective tissue alongside the trachea, a large axillary in the axillary fossa, a large brachial on the belly of the biceps muscles, a large inguinal adherent to the skin of the groin, and a small sciatic buried between bundles of the gluteal muscles near the emergence of the sciatic nerve.
Most of the nodes of the viscera are not bilateral, although some are on or near the midline. The principal nodes are three or four mediastinal near the thymus and bifurcation of the trachea; two pyloric (pancreatic) attached to the anterior margin of the pancreas near the pyloric end of the stomach; left and right renals between aorta and kidneys, the left being anterior to the renal vessels and the right partly obscured by the renal vessels passing ventral to it; a mesenteric, usually single and elongated, in the mesentery of the ascending colon; two small lumbars anterior to the bifurcation of the abdominal aorta, the left being smaller and more posterior than the right; and a single small caudal just posterior to the bifurcation of the abdominal aorta.
Microscopic anatomy. A fibrous capsule, a marginal subcapsular sinus, a cortex of dense lymphatic tissue, and a medulla of diffuse lymphatic tissue with a large intercommunicating sinusoids are constant features of all nodes. Reticular fibers and cells form the framework in which the lymphocytes are massed, and flattened reticulum (littoral) cells line the sinusoids. Indistinctly outlined nodules of lymphatic tissue, occasionally with pale centers (secondary or germinal centers), are transitory structures in the cortex. The boundary between cortex and medulla is often obscured by an intermediate zone of diffuse tissue which in old mice may be composed largely of plasma cells ( Dunn, 1954). Afferent lymph vessels open through the capsule into the marginal sinus; efferent vessels leave the node at the hilus where blood vessels enter and leave. The lining of postcapillary veins is unusual in that the cells are cuboidal and have distinct histochemical features ( Smith and Hénon, 1959).
The nodes have been classified into three types according to relative amounts and arrangements of cortex and medulla ( Dunn, 1954). In nodes such as the inguinal, the cortex surrounds the medulla, except at the hilus, and the intermediate zone is wide. The cortex and medulla are at opposite poles in nodes of a second type, represented by the lumbar node. In the mesenteric node, the third type, the cortex and intermediate zone are narrow and eccentric and the medulla wide with large sinusoids.
Gross anatomy. Although scattered foci of lymphatic tissue may occur anywhere in the walls of the respiratory, urinary, reproductive, and digestive tracts, aggregates of lymphatic nodules are found only in the small intestine, cecum, colon, and rectum ( Figure 13-36B). The conspicuous nodules on the antimesenteric wall of the small intestine are the Peyer's patches or intestinal tonsils. They vary in size with environmental conditions and in number with strain ( Kelsall, 1946; Hummel, unpublished, Table 13-1).
Microscopic anatomy. The peripheral nodules differ from nodes in having no capsules, marginal sinuses, afferent lymph vessels, nor definite cortical and medullary areas; otherwise they are structurally similar accumulations of lymphatic tissue.
The spleen, although composed chiefly of lymphatic tissue, is not classed with lymph nodes and peripheral nodules because it is neither in the course of lymph vessels nor at their beginnings. Instead, the spleen is in the course of blood vessels and has no lymph vessel connections.
The spleen is a slightly curved, elongated oval organ lying diagonally in the left anterior quadrant of the abdominal cavity along the greater curvature of the stomach ( Figure 13-4). The splenic artery enters through several branches along a longitudinal ridge on the dorsal aspect. The ventral aspect is very slightly convex; a cross-section through the central portion of the spleen is roughly triangular, the dorsal ridge forming the apex ( Figure 13-5). The spleen varies in appearance, shape, and size depending on age, strain, sex, and especially environmental conditions. The healthy spleen is deep red in color and has a smooth glistening surface. The right extremity is usually rounded but the left may be rounded, pointed, or bifurcated ( Table 13-2). Variation in size is so great that spleen weight is not a useful indicator of response of lymphatic tissue to experimental manipulations ( Dunn, 1954; Santisteban, 1960). One or more nodules of accessory splenic tissue are more often embedded in nearby pancreas. Strains of mice have been found to differ with respect to the percentage of individuals having accessory nodules (Hummel, unpublished, Table 13-2).
The surface layer is peritoneum, beneath which is a thin but tough elastic capsule of dense connective tissue containing some elastic fibers. Irregularly arranged thin trabeculae containing smooth muscle cells project inward, and with a network of reticular fibers and cells form the framework for the white and red splenic pulp. White pulp, lymphatic tissue sheathing small arteries, makes up the bulk of the organ. In white pulp, lymphocytes are massed into indistinctly outlined nodules, the splenic nodules or Malpighian corpuscles. They are similar to the cortical nodules of lymph nodes and like them are transitory structures occasionally exhibiting pale secondary or germinal centers. Marginal zones of diffuse lymphatic tissue surround the nodules, separating them from the red pulp which contains erythrocytes in the meshes. In mice of some strains, anastomosing clefts between the nodules and marginal zones have been described ( Snook, 1950). In addition to erythrocytes, red pulp contains granular leukocytes, lymphocytes, blood-forming elements, mast cells, plasma cells, and megakaryocytes. Extramedullary hematopoiesis is found regularly in the red pulp, erythropoiesis being especially evident in young healthy mice ( Dunn, 1954).
The complex vascular arrangement has been the object of much study and controversy. Transillumination of living spleens resulted in divergent opinions with respect to a closed (through sinuses) or open (through tissue spaces) circulation. Snook ( 1950), after studying graphic reproductions of spleens of many mammals, concluded that both types of circulation exist. Whereas man and the rat are in the "sinusal" group, the mouse belongs in the "nonsinusal" group. The red pulp of spleens of rat, dog, man, and many other mammals contains an elaborate plexus of sinuses; that of mouse, cat, pig and others has no true sinuses and relatively few veins leading from the meshes into collecting veins.
After entering the spleen, arteries branch repeatedly, decrease in size, and become ensheathed by splenic nodules. The small branched arteries extend from the white pulp into the red pulp where they divide into short straight penicilli. The penicilli of the mouse (and rat) do not have ellipsoid sheaths characteristic of their structure in spleens of man. Zones of red pulp with many erythrocytes in their meshes intervene between the ends of the penicilli and the capillary venules leading to collecting veins ( Snook, 1950).
There are strain differences in the pattern of the reticulum and its arrangement within the nodule, the relative amounts of red and white pulp, amount of hematopoiesis, numbers and distribution of hemosiderin-containing macrophages, and numbers of such cells as mast cells and megakaryocytes ( Dunn, 1954).
The thymus, long regarded as a vestigial organ with little or no function in the adult animal, has been classed with lymph nodes and spleen as an organ of reticular tissue and with other pharyngeal derivatives as an endocrine gland. The thymus differs from lymph nodes and spleen in being epithelial in origin and character and in having no sinusoids, and from endocrine glands in having no proved hormone-secreting activity. Recognition of the important role of the thymus in leukemogenesis (in the mouse) and in immunobiology has kindled interest in its form as well as its function. For studies on morphology the mouse thymus is ideal, having few lobules and a relatively simple vascular pattern ( Smith, 1964).
The thymus consists of two separate lobes located close together on either side of the midline in the anterior portion of the thoracic cavity ventral to the base of the heart and aortic arch ( Figure 13-4). In young mice the lobes are white and firm with smooth surfaces and few lobular indications. The two lobes differ in shape and the right more oval slightly overlaps the left more triangular one. The hilus where blood vessels enter and leave is a narrow inconspicuous cleft, variable in location but usually on the dorsolateral surface ( Smith et al., 1952). The thymus is larger in young than old mice, reaching the maximum absolute size at about the time of sexual maturity and thereafter declining ( Smith and Ireland, 1941). Decrease in weight is rapid between 35 and 80 days, but becomes gradual later. Although complete involution does not occur in old age, there is a decrease in all dimensions and the lobes become thin and leaflike ( Smith et al., 1952).
The thymic lobes are epithelial thickenings in the region of third and fourth pharyngeal pouches in 11-day embryos. During the 15th day the epithelial vesicles separate from the pharyngeal epithelium and come to lie anterolateral to the heart and during the subsequent 4 days they grow, migrate posteromedially, and become lymphoidal ( Auerbach, 1960).
Each lobe is composed of a dense cortex surrounding a pale irregularly arranged medulla ( Figure 13-6). The connective tissue capsule is thin and fibrous, and the septa which extend into the cortex at irregular intervals are inconspicuous and usually fail to reach the medulla. The stroma is a network of reticular fibers closely associated with blood vessels, and the parenchyma consists of a mass of cells classified on the basis of their appearance in the electron microscope into "lymphoid" cells, macrophages, and epithelial cells ( Clark, 1963). The latter, derived presumably from either endoderm or ectoderm of the pharynx, are distinguishable from the macrophages (mesenchymal reticular cells of Smith, 1964) by their ultrastructure. The "lymphoid" cells or thymocytes are indistinguishable from the small, medium, and large lymphocytes of nodes and spleen.
The epithelial cells and reticular fibers of the cortex are concealed by the densely packed masses of small lymphocytes. These cells, shown by tissue culture and transplantation techniques to be of epithelial origin, may be the precursors of all lymphocytes in nodes and spleen ( Auerbach, 1964). As there are fewer lymphocytes in the medulla, the large pale-staining indistinctly outlined epithelial cells with their pale spherical nuclei are visible, arranged in cords and small groups. Small cysts lined with cuboidal or ciliated mucus-secreting cells are frequent components of the medulla; they have been interpreted as secretory units ( Arnesen, 1958). The large macrophages with inclusions of phagocytosed debris are components of medulla, cortex, and surrounding connective tissue. Postcapillary veins in the cortex are lined as in lymph nodes, by tall endothelial cells ( Clark, 1963). The presence of sheathlike intrathymic lymph vessels accompanying large veins and arteries of the medulla ( Smith, 1964) has been denied by Clark, who observed large spaces often packed with lymphocytes but saw no endothelial lining. Medullary structures composed of one or two hypertrophied epithelial cells resemble Hassall's corpuscles of the thymus of man but do not form keratin.
With normal aging and after irradiation, the cortex becomes narrow and less cellular and large foamy chromolipoid cells appear near blood vessels and beneath the capsule, often accompanied by accumulations of mast cells. With age the vascular pattern changes, collagenous and argyrophil fibers increase around blood vessels, thymic cysts increase in number, plasma cells accumulate, and in old age, the thymus becomes almost entirely replaced by lobules of fat ( Smith, 1964).
These structures belong to no particular anatomical system, but each is sufficiently prominent to warrant description. Included are fat organs (aggregations of white and brown fat), the Harderian gland, and the lacrimal gland.
Both white and brown fat are found as discrete bodies with predilections for specific sites, and with functional attributes of organs.
White fat bodies.
Although fat cells may develop and accumulate anywhere within areolar connective tissue at any time during life, certain depots of fat are of constant appearance in specific sites. Among these are aggregations along blood vessels in the mesenteries, around kidneys and adrenals, attached to the gonads and excretory ducts, and in subcutaneous tissue of inguinal and axillary regions. There is compelling evidence that these aggregations of fat cells are specific embryonically determined structures and that genetic and sex influences may have important roles in their physiology ( Liebelt, 1959).
White adipose tissue is modified connective tissue appearing in fixed sections as a lacework of spherical or polyhedral cells in which the cytoplasm has been almost entirely replaced by fat and the nuclei are pressed against the cell membranes. Interspersed among the fat-laden cells are others with light-staining cytoplasm and centrally located oval nuclei. A delicate reticular framework surrounds the cells and supports the capillary network.
Brown fat organs.
This type of adipose tissue is morphologically, histogenetically, and physiologically distinct. The compact light brown bodies develop from specific embryonic anlagen, and no new areas appear postnatally ( Fawcett, 1952). Among the most conspicuous are lobes between the scapulae, in the axillae, in the cervical region along jugular veins, adjacent to the thymus, along the thoracic aorta, and the kidney hilus, and alongside the urethra. The relatively large paired lobes in the interscapular depression have been called hibernating glands and have been classified as endocrine organs. The brown fat is a form of adipose tissue physiologically more active than white fat, but there is no evidence that it secretes hormones and it does not function as an organ of hibernation in the mouse ( Fawcett, 1952).
Brown adipose tissue is composed of groups of polygonal cells containing lipid droplets in a coarsely granular cytoplasm. The fat droplets are not coalescent and the nuclei are central. The cells are surrounded by prominent, relatively coarse reticular fibers and numerous capillaries. The cells are unusually rich in phospholipids, and contain glycogen deposits under certain conditions ( Sidman and Fawcett, 1954).
Gross anatomy. The Harderian is a large horseshoe-shaped gland located deep within the orbit. A small superior arm is connected to a large inferior arm by a narrow band medial to the optic nerve. A single excretory duct opens at the base of the nictitating membrane. The color of the gland varies from pink to dark grey depending upon the abundance and characteristics of melanocytes in the capsule and interlobar septa ( Markert and Silvers, 1956). In addition the gland is speckled with a pigment identified as a porphyrin that fluoresces under ultraviolet light. There is evidence that this pigment is produced as well as excreted by the gland ( Cohn, 1955), and the amount is said to vary with strain, sex, and age ( Figge and Davidheiser, 1957).
Microscopic anatomy. The tubuloalveolar gland is covered by a delicate connective tissue capsule bound loosely to the orbital fascia. Strands from the capsule divide the gland into lobes and lobules. The epithelial cells are pyramidal, their height depending upon the secretory phase. A round nucleus containing two or three nucleoli is located near the base, and the cytoplasm, packed with lipid droplets, appears vacuolated ( Figure 13-7). Myoepithelial cells are present between the epithelial cells and the prominent basement membrane ( Chiquoine, 1958). The lamina propria is delicate fibrous connective tissue and among its cells are the melanocytes with nonfluorescent pigment. The secretion in the lumina of the tubules is oily and occasionally a yellow or reddish-brown color. Pigmented secretion may be present also in the lumina of the ducts which are lined with cuboidal epithelium. Alveolar, lobular, and lobar ducts join to form a single excretory duct.
There are two pairs of lacrimal glands, the exorbital located subcutaneously ventral and anterior to the ear, and the intraorbital at the outer canthus where the joint excretory duct opens. The glands are tubuloalveolar and structurally identical. Each is enclosed in a connective tissue capsule and divided by connective tissue septa into lobes and lobules. The aveoli are larger and more loosely arranged than those of the parotid gland which they resemble ( Figure 13-8). The secretory cells are pyramidal with granular basophilic cytoplasm that stains intensely near the round basally located nuclei and much less intensely between the nuclei and the narrow lumen. Myoepithelial cells are found between the epithelium and the basement membrane. The intralobular ducts are lined by cuboidal cells without basal striations, and the excretory duct by stratified columnar epithelium.
The endocrine or ductless glands are but one part of a complex neurosecretory apparatus that regulates countless body functions. Only the glands or parts thereof that are discrete endocrine units are described in this chapter. These include the thyroid, parathyroids, adrenals, pituitary (hypophysis), pineal (epiphysis), and the islets of Langerhans. The testis and ovary, which have exocrine as well as endocrine functions, are described under male and female genital systems. For discussions of endocrine interactions and concomitant histological variations see Chapter 20.
Gross anatomy. The thyroid gland consists of two elongated oval lobes, one on each side of the trachea, joined near their posterior poles by a thin isthmus crossing the trachea ventrally. The lobes, buried under the muscles of the neck region, are richly vascularized and made up of groups of hollow spheres often visible macroscopically. The lobes extend anteriorly as far as the cricoid cartilage of the larynx and posteriorly over the first three or four tracheal rings. Variations in size, extent, and position are common.
The gland is made up of hollow spheres or follicles of varying size surrounded by a fibrous connective tissue capsule and supported by richly vascular interfollicular connective tissue ( Figure 13-9). The follicles are lined by simple cuboidal cells having distinct outlines, large spherical nuclei, and clear cytoplasm. The central cavities contain varying amounts of colloid. The height of the epithelial cells and the amount and staining quality of the colloid are indications of secretory activity.
In young mice the follicles are uniform in size, are lined by tall cuboidal cells, and contain homogeneous slightly acidophilic colloid. During the early postnatal months (1 to 3 months in mice of strain C3H and 1 to 5 months in those of strain C57), there is a rapid decrease in cell height and an increase in follicle diameter ( Jacobs, 1958). With increasing age follicles become large and more variable in size, the interfollicular tissue decreases, and the colloid becomes more eosinophilic. Senile changes, which occur as early as 12 months in mice of some strains and are more marked in females, include loss of stainable colloid, increase in fibrous interfollicular connective tissue, and great variation in follicle size with coalescence of contiguous large follicles to form bilocular and trilocular cysts with flattened epithelium ( Andrew and Andrew, 1942; Blumenthal, 1955).
The thyroid gland develops from a medial epithelial mass growing ventrally at the level of first and second pharyngeal pouches. Thus, it is not surprising that aberrant thyroid follicles are occasionally found in regions both anterior and posterior to that described above ( Hunt, 1963). Ultimobranchial tissue from pouches IV and V normally becomes closely integrated with the median mass and may form structures that persist in the adult thyroid, some of which are physiologically as well as morphologically distinguishable from the medially derived thyroid ( Gorbman, 1947). Ultimobranchial follicles are recognized by the presence of ciliated epithelial cells. Cysts with ciliated epithelium are particularly conspicuous in strain C3H where they have been observed in newborn mice ( Dunn, 1944).
Thyroid function is initiated in 15- to 17-day fetuses and observations indicate that colloid secretion precedes follicle formation ( Van Heyningen, 1961).
Gross anatomy. The position as well as the number of parathyroid lobes is variable, although usually a single lobe lies just under the capsule near the dorsolateral border of each lobe of the thyroid. Two members of a pair are seldom at the same anteroposterior level; sometimes one or both may be posterior to the thyroid ( Dunn, 1949b); they may be deeply embedded in the thyroid tissue; and there may be more than two.
Microscopic anatomy. Each parathyroid gland is separated from the thyroid by a connective tissue capsule and consists of sheetlike masses and anastomosing cords of polygonal cells separated by a network of capillaries or sinusoids ( Figure 13-9). Two or three cell types can be recognized, their relative abundance varying with age ( Foster, 1943; Blumenthal, 1955). The principal cells have large vesicular nuclei and scanty basophilic cytoplasm. Ovoid-to-fusiform-shaped cells with smaller more hyperchromatic nuclei and more abundant granular eosinophilic cytoplasm occur in small groups in the interstitial connective tissue. These increase in number with age. Very large cells with large vesicular nuclei and prominent nucleoli become conspicuous only in old age ( Blumenthal, 1955). Pigmented dendritic cells may occur in the parathyroid stroma of pigmented mice and have been seen most frequently in mice of strain C58 ( Dunn, 1949b).
The parathyroid glands develop from the third and fourth pharyngeal pouches in close proximity to the developing thymus, ultimobranchial bodies, and thyroid, with any or all of which they may remain in contact in the adult. Parathyroid rests, distinguishable histochemically, have been found consistently in the thymus septa or surface connective tissue ( Smith and Clifford, 1962), and parathyroid, thyroid, and thymus are sometimes connected by a ciliated cyst ( Gorbman and Bern, 1962).
Gross anatomy. The adrenal glands are a pair of small ovoid structures situated one on either side of the midline near the anterior pole of the kidney. The right and left adrenals differ in respect to closeness to kidney, renal vessels, and inferior vena cava; strain differences in these respects have been observed ( Hummel, 1958). The glands of males and females differ in size and appearance, those of females being consistently larger and more opaque due to the presence of more lipid.
The adrenal gland consists of two parts, cortex and medulla, each with a separate origin, structure, and endocrine function. The cortical anlagen develop in the mesodermal coelomic epithelium near the genital ridges at about the 12th day, the medullary anlagen from sympathetic nervous system ganglia at the 13th day, and the first signs of union of the two occur at about the 14th day ( McPhail and Read, 1942). Accessory units of cortical and medullary (chromaffin) tissue in scattered small groups near the left renal vein ( Coupland, 1960) and cortical nodules near the kidneys and adrenals on both sides ( Hummel, 1958).
Microscopic anatomy. The cortex is surrounded by a fibrous connective tissue capsule often laden with adipose cells. In man and most mammals three zones are visible in the adrenal cortex, but in the mouse only two zones are clearly defined ( Figure 13-10). The outer glomerulosa is a narrow zone consisting of small cells arranged in arches. The cells have relatively large nuclei, basophilic cytoplasm, and a rich capillary blood supply. Internal to the zona glomerulosa is the wide zona fasciculata, composed of radial columns of cells separated by fine connective tissue septa bearing capillaries. The nuclei are vesicular and the cytoplasm acidophilic and foamy due to the presence of finely distributed lipid droplets. Although some investigators describe an inconspicuous third zone, the reticularis, others question its existence ( Jones, 1950; Miller, 1950). In young nulliparous females and in males prior to sexual maturity, there is a zone of variable width between cortex and medulla. This juxtamedullary zone, the X-zone, disappears with sexual maturity in the male and with first pregnancy in the female. It persists in castrated males and in virgin females for periods varying with strain ( Delost and Chirvan-Nia, 1958).
Certain conspicuous changes occur with age. A proliferation of small spindle-shaped cells starts between capsule and zona glomerulosa and spreads laterally and centrally tot he juxtamedullary zone. Large multinucleate foamy cells bearing brown pigment appear in the juxtamedullary zone and central portions of the fasciculata zone. This "brown degeneration" is believed identical to that in aged ovaries; the pigment resembles ceroid ( Jones, 1950; Deane and Fawcett, 1952).
The medulla consists of homogeneous polyhedral cells arranged in irregular groups separated by sinusoids ( Figure 13-10). Nuclei are large and centrally located, the cytoplasm lightly basophilic and finely granular. The medullary cells have an affinity for chromium and are thought to be a special type of neurosecretory cell. Erythropoietic foci are common in adrenals in newborn mice as well as in adult mice under certain pathological conditions ( Borghese, 1952).
Gross anatomy. The pituitary gland or hypophysis rests on the dorsal surface of the basisphenoid bone of the skull and is attached to the floor of the brain by a fragile stalk ( Figure 13-11). The gland is slightly flattened dorsoventrally and has an elongated oval shape with its long axis perpendicular to that of the head. The ventral surface is well vascularized and homogeneous and the dorsal surface is demarcated into three distinct regions ( Figure 13-12). The central and most opaque is the pars nervosa (neural lobe), which is derived embryologically from the floor of the third ventricle of the brain. Bordering the pars nervosa is the slightly less opaque narrow pars intermedia (intermediate or proximal lobe) and, outside of this, extending far laterally and covering the other lobes ventrally, is the well-vascularized pars distalis (anterior or distal lobe). The latter two lobes are derived from Rathke's pouch, a thickening and evagination of the ectoderm of the roof of the mouth cavity where this is in close proximity to the developing brain. The pars nervosa loses its central cavity but remains attached to the hypothalamus of the brain by a thin stalk. The other lobes lose their connection with the oral cavity, the only remains of Rathke's pouch being a residual cleft separating pars intermedia and distalis (Figures 13-13, 13-14). The inconspicuous tuberalis is the small part of the anterior lobe partially wrapped around the stalk. The development of the pituitary has been studied and described in detail ( Kerr, 1946).
The pituitary gland is consistently heavier in females than in males and there are also strain differences in size. The average weight of the pituitary of the adult female exceeds that of the male of the same age and strain by 0.5 to 1.5 mg ( Chapter 20).
Microscopic anatomy. The pars nervosa is made up of endings of neurons, glial cells, ependymal cells, and connective tissue supporting capillaries and sinusoids. Cell bodies of neurons are seldom seen. The lining cells of the sinusoids are phagocytic.
The border between neural and intermediate lobes is uneven and indistinct ( Figure 13-14). The cells of the pars intermedia are arranged in groups separated by fibrous connective tissue strands with scarce vascular elements. Most of the cells are polygonal with pale-staining nongranular basophilic cytoplasm and densely staining oval nuclei. A few stellate cells with long processes are interspersed. The intermediate lobe of the mouse is wide compared to that of some mammals; it is especially wide and conspicuous in mice of strain 129.
The pars intermedia and pars distalis are separated by the residual cleft, lined throughout by low cuboidal epithelium ( Figure 13-14). In the pars distalis, the largest and most vascular of the lobes, the cells are arranged in branching cords separated by sinusoids and are of several cytological types. The cells do not stain differentially as readily as in some other mammals, special techniques being required to bring out cytological details. Chromophobe cells with large light-staining nuclei surrounded by small amounts of nongranular cytoplasm make up about 50 per cent of the population, the rest being chromophils of three types ( Halmi and Gude, 1954). The most common chromophil is the acidophil, a small round or oval cell with a centrally located nucleus and eosinophilic cytoplasm, which makes up about 40 per cent of the whole. The smallest group, making up less than 11 per cent, is composed of beta and delta cells, formerly classed together as basophils. The beta cells are angular or crescentic, have coarse aldehyde-fuchsin-positive granules, are most numerous in the central portions of the lobe, and are more numerous in males that in females. The delta cells are small with aldehyde-fuchsin-negative granules and are more numerous in females. Others have classified the cells of the pars distalis into acidophils and amphophils (cells that show affinity for aniline blue) and described a transformation from one to the other ( Van Ebbenhorst Tengbergen, 1955). Cysts of varying size, often lined with ciliated epithelium and containing eosinophilic secretion, occur frequently.
Gross anatomy. The pineal gland or epiphysis is a very small cone-shaped body situated on the dorsal surface of the brain between cerebrum and cerebellum, with the peak of the cone directed anteriorly ( Figure 13-15). The attachment to the brain stem is long, extremely delicate, and filmy; if the roofing bones of the skull are removed, the epiphysis remains attached to them at the suture between parietal and interparietal bones. The pineal develops from a medial evagination of the roof of the third ventricle of the brain into a well-vascularized area and in the adult retains an association with the richly vascular cells of the choroid plexus. The blood supply, however, is independent of that of choroid plexus and brain ( Von Bartheld and Moll, 1954).
Microscopic anatomy. The thin fibrous capsule surrounding the gland merges with cells of the choroid plexus. The gland is complex histologically and contains ependymal, glial, neuronal, and other elements in a richly vascular framework ( Figure 13-16). Two types of cells can be identified: large indistinctly outlined spherical cells with pale, slightly granular, basophilic cytoplasm and large vesicular nuclei with prominent nucleoli; and elongated stellate cells with deeply staining basophilic cytoplasm and oval nuclei with fine chromatin granules.
Islets of Langerhans
Gross anatomy. The islets, distributed among the exocrine secretory aveoli of the pancreas, are not visible macroscopically under normal conditions. The solid spherical groups of cells are always closely associated with pancreatic ducts and blood vessels of the connective tissue septa ( Figure 13-40).
Microscopic anatomy. The islets vary considerably in size and are distinguishable from pancreatic alveoli by their pale-staining quality. The cells, grouped in irregular cords about sinusoids, are round, polyhedral, and cuboidal and have round, faintly staining nuclei. Special staining techniques allow identification of as many as four types of cells based on differences in cytoplasmic granules. Cellular differentiation from 13 days of gestation to the adult has been described ( Munger, 1958).
SKIN AND DERIVATIVES
Derivatives of the skin are pelage hairs, sensory or tactile hairs, sebaceous glands, and mammary glands. Another skin derivative, the sudoriferous gland, is reportedly absent in the mouse ( Hardy, 1949) although rudimentary and transitory tubules resembling these glands have been observed ( Gibbs, 1941).
The skin covers the entire outer surface of the body and, except in certain regions and in mice of certain genotypes, bears hair over the greater part. Hairless skin surrounds and extends a variable distance into all external openings (nipples, nostrils, mouth, urethra, vagina, and anus). The skin consists of two parts, an outer epidermis of stratified squamous epithelium and an inner dermis or corium of dense connective tissue, continuous with adipose and loose connective tissue of the subcutaneous areas.
Epidermis. The epidermis is thin in haired areas and considerably thicker on the hairless or relatively hairless portions such as feet, tail, snout, nipples, and genital and anal areas. In these thick areas there are three or more strata, each of several cell layers. The basal layer, stratum germinativum, rests on a basement membrane and consists of vertically compressed cells with indistinct cell outlines and clear oval nuclei, plus several layers of polyhedral cells connected across intercellular spaces by tonofibrils. The next four or five layers of cells, which are compressed horizontally and may contain coarse keratohyalin granules, make up the stratum granulosum. The outermost stratum corneum is composed of several layers of dead cornified cells that are shed at the surface and replaced from deeper layers.
In haired areas the epidermis rarely exceeds six cell layers and the strata are hard to define. The basal cells of the germinativum are cuboidal, the stratum granulosum is represented by a few scattered cells, and there are only one or two layers of cells in the stratum corneum. The epidermis is well developed at birth, becomes thicker during the first 4 or 5 days after birth, and then decreases in conjunction with hair-follicle development ( Gibbs, 1941). There are no blood vessels or nerves in the epidermis, and, although melanocytes potentially capable of producing pigment are scattered among the basal cells, pigment is usually not detectable in epidermal cells ( Billingham and Silvers, 1960).
Dermis. The connective tissue of the dermis contains collagenous and elastic fibers, blood vessels, nerves, fat cells, and strands of smooth muscle (arrector pili). In head, neck, and trunk regions thin sheets of striated muscle (the panniculus carnosus) insert on the fibers of the dermis at its boundary with the subcutis.
Branched melanocytes containing pigment are cellular components of the dermis in pigmented areas such as muzzle, ears, soles of feet, tail, genital papilla, and scrotum; but are not demonstrable in the dermis of haired areas ( Billingham and Silvers, 1960). Where the epidermis is thick, the epidermodermal boundary is very uneven, the dermis with its blood vessels and nerves being extended into the epidermis in tall elevations or papillae. In haired areas dermal papillae are inconspicuous and the boundary between dermis and epidermis is only slightly uneven. The loose connective tissue on which the dermis rests becomes transformed soon after birth into an adipose layer of packed fat cells.
Hair and sebaceous glands. Hair follicles are invaginations of epidermis into the dermis giving rise to hair, both pelage and tactile, and to sebaceous glands.
Pelage hair. Mouse hairs and hair follicles are similar structurally to those of other mammals. The hair projecting above the skin surface is a three-layered column or shaft of cornified cells consisting of an outer cuticle of translucent scales, a cortex of elongated cells or septa containing small amounts of pigment, and an inner core or medulla of irregularly shaped septa containing pigment granules. Below the skin surface the hair shaft is enclosed in a double sheath or follicle at the base of which the hair matrix is formed by proliferation of epidermal cells. In development of the hair follicle, the basal layer of the epidermis thickens, grows into the dermis, and forms a bulb over a core or papilla of dermal cells. The external root sheath of the follicle is derived from the downgrowing epidermal cells; the internal root sheath, hair matrix, and hair shaft arise from actively dividing cells of the bulb area. The follicles are not perpendicular to the skin surface but slant obliquely toward the posterior. A single sebaceous gland develops in the obtuse angle between follicle and epidermis by proliferation and evagination of epidermal cells of the external sheath. A strand of smooth muscle fibers (arrector pili muscle) forms in the dermis, extending from the follicle just below the sebaceous gland to the epidermodermal junction. As the basal epidermal cells push into the dermis they carry melanocytes which produce pigment in this environment. The melanocytes become concentrated in the hair bulb where pigment granules are transferred to the growing hair shaft by some undetermined process. The number, size, shape, clumping pattern, color, and color intensity of the pigment granules in the medullary septa all contribute to the definitive coat color ( Russell, 1946; Chapter 21).
There are several types of hair in the coat and for each there is a hair follicle that produces the one type only. Hairs were first classified by Dry ( 1926) into overhairs (monotrichs, awls, and auchenes) making up about 16 per cent and underfur (zigzags) about 84 per cent of the coat, on the basis of such characteristics as length, number of bends of constrictions in the shaft, and number of rows of septa in the medulla. The monotrichs, also called guard hairs, are the long straight tylotrichs, classified and described below as tactile hairs. The awls are straight hairs, auchenes have a single bend, and zigzags have several bends. Awls may have as many as four, usually have three, and always have at least two rows of medullary septa. Auchenes have two septal rows, seldom more, and zigzags only one row.
Initiation of follicle formation has been reported to occur in the 14-day embryo and to continue until 9 days after birth (see Chase, 1954). However, Mann ( 1962) observed first pelage follicles at 16 ¼ days and no new follicle initiation after birth. Initiation of all follicle types occurs first in the shoulder region; spreads in a wave anteriorly, caudally, ventrally, and dorsally; and is completed everywhere before birth. First initiation of awl follicles occurs in 16 ¼-day embryos, and of auchene and zigzag follicles in 18 ¼ -day embryos. The duration of development is approximately the same for all follicle types; hairs emerge through the skin surface 8 to 9 days after initiation of the follicle ( Mann, 1962). Cycles of hair growth subsequent to first coat emergence occur throughout life with periods of active growth of 17 to 19 days alternating with resting phases of variable duration, during which old hairs are retained in the follicles as dead clubs ( see Chase et al., 1951, for growth stages). Individual follicles do not enter the growth phase independently of neighboring follicles. instead, all follicles within a particular area enter the growth phase of the cycle synchronously resulting in orderly waves or spreads of hair growth and hair follicles activity. Chase and Eaton ( 1959) studied the wave patterns over five generations of hair in male and female mice of four inbred strains and found that patterns varied with strain, sex, and age, as well as in individual mice.
During cycles of hair growth, changes take place in the skin and sebaceous glands ( Chase, 1954; Borodach and Montagna, 1956). During active hair proliferation the capillaries around the follicle become enlarged, the dermis and adipose layers thicken, the epidermis becomes thin, and the sebaceous glands small. Although dermal papillae are necessary in the production of hair, they contain few if any capillaries at any stage.
Tactile hair. Sensory or sinus hairs differ from pelage hairs in several respects: they are larger and longer; their tips contain little pigment, and in agouti mice they lack they yellow band. The follicles are large and contain blood sinuses and abundant nerve endings ( Figure 13-17); and dead club hairs are not retained in the follicles. There are two types of tactile hairs: the vibrissae located almost exclusively on the face, and the tylotrichs (monotrichs or guard hairs) scattered among the pelage hairs.
Patterns of major and minor groups of vibrissae have been plotted for mice of different genotypes ( Davidson and Hardy, 1952; Dun, 1958). Those in the major group are in five horizontal rows and one vertical row on the snout and three rows on the lower lip, but they vary in number and are difficult to count. There are usually 19 in the minor group which includes three interramals, paired supraorbitals (two in one tubercle), postorbitals (one), postorals (two), and ulnar carpals (three in a large tubercle). This pattern is fairly constant, postorbitals being invariably present and others rarely absent ( Dun, 1958).
The structure of the vibrissa hair is similar to that of the pelage hair except in size, length, and distribution of pigment. The vibrissa follicle is large and contains venous blood sinuses and nerve fibers within a heavy connective tissue (dermal) sheath ( Figure 13-18). Large capillaries are present in the papilla, and striated muscle fibers replace smooth muscle bundles. There is a single sebaceous gland for each as in pelage follicles. Vibrissa follicles are first to develop in the embryo and all vibrissae have emerged by birth. Initiation of vibrissa follicles is first observable during the 13th embryonic day and the hairs emerge 5 to 6 days later. For detailed descriptions of the structure and development of vibrissa follicles and vibrissae see Melaragno and Montagna ( 1953) and Davidson and Hardy ( 1952).
Tylotrichs are the monotrichs of Dry ( 1926) and the guard hairs of others. They are scattered singly among the shorter awls, auchenes, and zigzags of the trunk, and small hairlets are associated with some of them. Although recognized as tactile hairs, they were classified as pelage hair until their similarity to vibrissae and to tylotrichs of other mammals made reclassification desirable ( Straile, 1960). Tylotrich hairs are long and straight with a graduated tip that projects above the other coat hairs. There is but one hair in each follicle, dead club hairs not being retained, and there are two sebaceous glands for each follicle. Embryonic development of a tylotrich follicle starts as a raised area on the epidermal surface, in contrast to the basal-cell downgrowth of pelage follicles ( Mann, 1962). Part of this epidermal thickening becomes the Haarschiebe, an acentric thickening of the epidermis of the follicle orifice and a distinguishing characteristic to the tylotrich.
Initiation of tylotrich follicles starts as does that of pelage follicles in the shoulder region and spreads similarly in a wave. Initiation starts in 13 ¼-day embryos and is completed 2 to 3 days later at about the time initiation of awl follicles starts ( Mann, 1962). The hairs erupt 8 to 9 days after follicle initiation (about 3 days after birth).
Sebaceous glands. These glands, one to each pelage and vibrissa follicle and two to each tylotrich, develop as focal thickenings, cellular hypertrophies, and evaginations of the external root sheath into the surrounding dermis. Excretory ducts formed by canalization of the thickened area of the root sheath open into the space between hair shaft and follicle just below the orifice. The gland is a pear-shaped structure surrounded by a basement membrane and dermal connective tissue. There are two layers of cells, an outer basal layer of thin flat cells, and an inner layer of large rounded secretory cells. These latter accumulate secretion, die, disintegrate, and are replaced from the basal layer. If destroyed, sebaceous glands will redifferentiate from cells of the external root sheath but only while the hair is in the active growing phase ( Montagna and Chase, 1950).
For extensive reviews of the literature and of studies on the prenatal, prepuberal and postpuberal development and morphology of the mammary glands of mice, male and female, virgin and parous, see Raynaud ( 1961) and Cowie and Folley ( 1961).
Gross anatomy. Female mice normally have five pairs of nipples and mammary glands, three in the thoracic and two in the abdominal region ( Figure 13-19). (There is an additional abdominal pair in female rats.) When fully developed, the glands consist of extensive duct systems and lobules of secretory aveoli embedded in subcutaneous fat pads. Each pad is a separate unit branching from a primary duct that opens to the exterior at the tip of the nipple. The nipples are slightly depressed and are surrounded by circular folds of thickened hairless and sometimes pigmented skin; they are inconspicuous and obscured by hair except in infant mice and during late pregnancy and lactation. Variation in number and arrangement of nipples is frequent on some strains. For examples, fewer that five pairs are common in strain A females; more than five pairs in BALB/c females ( Little and MacDonald, 1945). Male mice have no nipples and usually only four pairs of rudimentary glands consisting of branching ducts with no aveoli, primary ducts, or openings to the exterior.
Mammary glands develop from lines of thickened epithelium overlying mesenchymal condensations on either side of the ventral midline. At about the 13th embryonic day, five pairs of anlagen or buds are formed on this line by proliferation of basal epidermal cells. During the 15th day, sex differences begin to appear coincident with differentiation of the fetal testis. The mammary bud lengthens in the female and grows into the mesenchyme as an epithelial cord that remains connected to the epidermis. Canalization of the cord takes place in the 16th and 17th days, resulting in a primary duct opening to the exterior. In the meantime nipples have become demarcated by invagination of epidermal cells encircling the mammary buds. At birth, the female gland consists of a primary duct opening through a nipple and branching distally into several secondary ducts.
In males, the mammary buds become separated from the epidermis by condensation of mesenchyme around the neck constricting it and are completely isolated from the epidermis by the 16th day. Further development is usually limited to formation of small epithelial cords and simple branching. Some buds such as the inguinal pair may degenerate completely. No invagination of epidermal cells occurs around the buds and thus no nipples are formed. The fetal testis is responsible for the separation of mammary buds from the epidermis and for the inhibition of development of the nipple ( Raynaud, 1961).
Mammary glands of prepuberal mice consist of branching ducts embedded in adipose tissue. The ducts are lined by low columnar or cuboidal cells with dark staining oval nuclei and small amounts of cytoplasm. There is often a layer or scattering of myoepithelial cells between the epithelium and basement membrane which show an intense alkaline phosphatase reaction ( Richardson and Pearson, 1954). Circularly arranged connective tissue fibers, thicker in the large main ducts than in the smaller terminal ones, complete the duct walls. Just before puberty, at 3 to 4 weeks of age, there is a period of rapid growth with elongation of ducts, development of side branches, and formation of end buds on the branches ( Figure 13-20). Postpuberal development reaches the maximum in virgin females of 4 to 7 months, and consists of further duct proliferation and the formation of a few isolated alveoli ( Nandi, 1958). There are strain differences in the extent of alveolar development in the glands of virgin females ( Richardson and Hummel, 1959). The glands of strain RIII virgins have few alveoli ( Figure 13-21A), whereas many glands of strain C3H and of hybrids between C3H and RIII contain lateral buds and clusters of alveoli ( Figure 13-21B, C) ( Richardson and Hall, 1960). Although hypertrophy and ductal dilatation take place during the first estrous cycles, biopsies of mammary glands of 3- to 7-month-old virgin females showed no cyclic changes ( Ferguson, 1956).
Complete lobuloalveolar development occurs only during pregnancy and lactation. During the first week of pregnancy many new end buds and alveoli appear, connective tissue increases around the ducts, and there are numerous mitoses in he epithelial cells of the alveoli ( Figure 13-22). Growth reaches a peak by the end of the second week when there are numerous lobules made up of alveoli lined with single layers of low columnar and cuboidal cells ( Wellings et al., 1960). Further development consists of enlargement of alveoli with increase in lumen size, hypertrophy of epithelial cells, and beginning secretory activity. Proliferation and enlargement of alveoli is accompanied by decrease in adipose tissue of the fat pad and increase in vessels of the capillary network. The secretion of milk starts in the alveoli near the nipple and is usually well established distally at term ( Figure 13-23).
By the fourth day of lactation, lobules of closely packed alveoli have replaced most of the adipose tissue, and alveoli and ducts are distended with milk ( Figure 13-24). The epithelial cells are low cuboidal and squamous with flattened nuclei. Although secretory activity with increased distension of alveoli and ducts is apparent throughout lactation, growth appears to have ceased. However, studies using DNA as an index of growth have shown that proliferation continues throughout pregnancy and at least to day 14 of lactation ( Brookreson and Turner, 1959).
Following the cessation of suckling, the glands remain congested with milk for 24 to 48 hours, and during this time alveolar epithelial cells have started to degenerate and are found detached in the lumina ( Figure 13-25). By the fifth postweaning day the glands are devoid of milk and the alveoli reduced to masses of cells without lumina ( Nandi, 1958). In the completely regressed and resting gland, capillaries are inconspicuous, adipose tissue fills the spaces between the irregular clumps of cells from collapsed alveoli, and the duct lumina are narrow. In old multiparous females, glands undergo gradual involution, distal duct branches becoming atrophic, leaving only the main ducts and a few secondary branches.
No lateral buds or alveoli ever develop on the ducts of normal male mice although the duct system may be extensive ( Figure 13-26). Glands of an individual seldom develop uniformly and strain differences in the extent and architecture of the duct systems have been noted (Richardson, 1951, 1953). Although the glands of most males are rudimentary or absent, some glands in males of a few strains have well-developed duct systems resembling those of virgin females except for absence of primary ducts.
Oral cavity and pharynx.
The oral cavity is bounded anteriorly by the lips, laterally by the cheeks, and posteriorly by the epiglottis and rim of the soft palate. The roof is formed by the hard and soft palates, and the floor by the tongue. The cavity is widest in the region of the molar teeth, narrowing anteriorly and posteriorly. The pharynx, a small chamber posterior to the oral cavity, is common to digestive and respiratory tracts. It has four openings: anteroventral into the oral cavity, anterodorsal into the nasopharynx, posteroventral into the larynx, and posterodorsal into the esophagus. The epithelium of the oral cavity is stratified squamous cornified throughout, as is that of most of the pharynx including extension into the nasopharynx and larynx.
Lips. The lips are covered externally with skin bearing short hairs and internally with hairless skin (mucous membrane). The upper lip is cleft, exposing the two upper incisor teeth; posterior to them the lip curls inward on each side, forming lobes with their hairy surfaces in contact with the dorsal surface of the tongue and their mucous surfaces with the palate. The lower lip partly conceals the lower incisor teeth and, at the angles of the mouth, turns upward along the cheeks, forming folds bearing hairs on the surfaces facing the cheeks and palate. The folds of upper and lower lips occupy the spaces (diastemata) between incisor and molar teeth. Large sebaceous glands are located at the angles of the mouth, their short ducts opening directly on top the mucous surface between lip fold and cheek.
Teeth. The dental formula is incisor 1/1, cuspid 0/0, premolar 0/0 and molar 3/3. The incisors are long and bow-shaped and have roots extending posteriorly, dorsal and ventral to the roots of the upper and lower molars. The pointed tips of the lower incisors lie slightly posterior to the blunted ends of the uppers when the mouth is closed. The incisors grow and are worn down continuously, the apical foramina remaining open. The crown on the outer convex surface is covered with enamel, whereas enamel is lacking on the inner concave surface and the dentine is covered with cementum.
The molars are similar structurally to those of man, and as in man the third molars are small and poorly developed. In one strain (CBA) the third molars are especially small and one or more are lacking in 18 per cent of the mice, the lower molars being more affected than the uppers ( Grüneberg, 1952). In mice with absent molars the germ develops normally until about the sixth postpartum day when it begins to regress ( Grewal, 1962). The cusp and root patterns of upper and lower molars differ, the uppers being more uniform with three cusps and three roots per molar ( Cohn, 1957). Upper and lower molars also differ in the direction of tilt, the uppers being tilted toward the cheek, the lowers toward the tongue ( Gaunt, 1961). The development of molar teeth, from initiation of tooth bud to eruption into the oral cavity and functional occlusion, has been described by Cohn ( 1957) and the development of enamel and dentine and their distribution on the crowns of the developing teeth described by Gaunt ( 1956). At the time of eruption the cusps are sharp and pointed and are linked by transverse ridges with deep clefts between them. Areas on the margins of the cusps and in the clefts (apical pits) are enamel-free. As the exposed dentine and surrounding enamel are worn down and the crown eroded by mastication, there is a compensatory deposition of cementum at the apical end of each root. In young mice before grinding has worn the surface, distinctive strain-limited cusp patterns can be identified (Bader, 1962, personal communication). Strain differences have been observed also in the trabecular pattern of the alveolar bone and in the thickness of the periodontal membrane ( Baer and Lieberman, 1959).
Tongue. The tongue extends from the epiglottis to the lower incisors. The distal portion anterior to the molars is not attached to the floor of the mouth; the proximal portion posterior to the molar teeth is attached at the sides and forms the floor of the mouth cavity. Except for a small area anterior to the epiglottis, the dorsal surface is roughened by the presence of many horny papillae. The ventral and lateral surfaces are smooth. Distinguishing features are the median dorsal groove at the tip, the abruptly rising median intermolar eminence, and the postmolar solitary vallate papilla.
The epithelium is thick stratified squamous cornified extended into papillae on the dorsal surface ( Figure 13-27). The most numerous of these are the conical papillae anterior to the intermolar eminence and the structurally identical filiform papillae posterior to it ( Kutuzov and Sicher, 1953). Their horny tips, formed by overlapping layers of cornified cells, point posteriorly. Giant filiform papillae are located in the depression just anterior to the intermolar eminence, their very horny tips being directed toward the center of the depression ( Figure 13-27). Less numerous mound-shaped fungiform papillae, formed of epithelium with cores of connective tissue, are scattered among the conical papillae. The vallate papilla with its connective tissue core is bounded laterally by deep curved troughs. Four or five rows of low foliate papillae, separated by shallow oblique furrows, are located on the sides of the tongue opposite the molar teeth.
Clusters of taste buds are numerous in the epithelium on both sides of the deep troughs of the vallate papilla, on the dorsal surface of the vallate papilla ( Figure 13-28A), and on the surfaces of the foliate papillae ( Figure 13-28B). The solitary taste buds of the fungiform papillae extend into the connective tissue cores ( Figure 13-28C).
The lamina propria, a narrow band of fibrous connective tissue between the epithelium and underlying muscle bundles, forms numerous interepithelial papillae producing an uneven waved epithelial border. The muscles, all striated, are both extrinsic and intrinsic, the former attaching to the hyoid bone, mandibles, and cartilages of the larynx. The muscle bundles are separated by thin sheets of fibroelastic and adipose connective tissue, supporting blood and lymph vessels, nerve fibers, and ganglia. Mast cells are a common constituent of the connective tissue. Serous glands (von Ebner's) are embedded in the muscles in the postmolar region ( Figure 13-28A). Their ducts open into the troughs of the vallate papilla. Numerous mucous glands open directly onto the dorsal surface posterior to the vallate papilla, and deeply embedded mucous glands open by long ducts into the shallow furrows of the foliate papillae.
Palate. The anterior hard palate, extending from the incisors to beyond the third molars, is firmly attached to the palatine processes of the premaxillary, maxillary, and palatine bones of the cranium. The hard palate bears eight rows of membranous ridges (rugae) formed by condensations of dense connective tissue continuous with the periosteal connective tissue. A short anterugal region posterior to the incisor teeth is covered with a many-layered, heavily cornified, stratified squamous epithelium. On either side of the midline just anterior to the first ridge are small openings guarded by folds of epithelium. These lead into narrow channels extending dorsally and anteriorly to the nasal cavities. The anterior three ridges are transverse and unpaired; the five posterior pairs are V-shaped and irregular but tend to meet in the midline. A bar of cartilage is contained within the connective tissue of the first ridge. Although the epithelium over the ridges is thick and cornified it does not project into spinous processes as in the rat. The postrugal region is short and bears numerous solitary taste buds in its epithelium ( Figure 13-28D) except in the median area opposite the vallate papilla.
The palate originates as a vertical shelf of tissue on each side of the tongue. Closure is accomplished in 14- to 15-day embryos by rapid movement from sagital to transverse planes and meeting and fusion of the palatine shelves ( Walker and Fraser, 1956). There are strain differences in the developmental age of palate closure according to these authors.
The soft palate is boneless, glandular, and flexible, forming not only the roof of the posterior oral cavity but also the floor of the nasopharynx ( Figure 13-29). The posterior border forms a semicircular arch (glossopalatine) around the opening of the oral cavity into the pharynx. Fibroelastic connective tissue underlies the epithelium of both surfaces, and striated muscle fibers lie beneath the nasopharyngeal surface in the posterior third of the palate. Numerous mucous alveolar glands surrounded by loose vascular connective tissue open through short ducts directly onto the oral surface.
Pharynx. The posterodorsal opening of the pharynx into the esophagus is depressed and continuous with deep channels on either side of the slightly elevated larynx. The epithelium of this region is thick stratified squamous with many layers of cornified cells. Solitary taste buds are scattered in the thinner stratified squamous epithelium of other regions of the pharynx. The lamina propria of the pharynx is dense and fibrous and merges with the connective tissue of striated muscle bundles of the neck and head regions.
There are three pairs of salivary glands (parotid, submandibular, and sublingual) located in the subcutaneous tissue of the face and neck. Each gland retains a connection with the oral cavity through a single excretory duct. None is a mixed gland, each being limited to one type of secretory cell, serous in the parotid and submandibular and mucous in the sublingual gland.
Gross anatomy. The parotids are diffuse lobulated glands that extend over a considerable area from the ears to the clavicles. Each gland is divided into lobules be delicate connective tissue septa that merge with the surrounding loose connective tissue. Anteriorly some of the lobules overlie the leaflike exorbital lacrimal gland ( Figure 13-8) and posteriorly others are in contact with the submandibular and sublingual glands ( Figure 13-30). A single excretory duct, formed by the union of interlobular ducts, extends anteriorly over the muscles of the jaw and opens into the vestibule of the oral cavity opposite the molar teeth of the lower jaw.
The large compact submandibular glands are located in the ventral neck region. They extend posteriorly to the sternum and clavicles, anteriorly to overlie the hyoid bone, and medially to meet or overlap slightly in the midventral line. The glands of males and females differ, those of males being larger and more opaque, but both are lobulated and well vascularized. A single excretory duct from the anterior dorsal surface of each gland extends anteromedially to open on the floor of the mouth just posterior to the incisor teeth.
The small compact flattened sublingual glands are pressed against the ventral anterolateral surfaces of the submandibular glands. Each is a single lobe subdivided into lobules and each has a single excretory duct that follows the submandibular duct, opening close to it, but separately, into the oral cavity.
Microscopic anatomy. The three glands have structural features in common. All are compound tubuloalveolar glands separated into lobules by connective tissue septa. The secretory alveoli are lined with tall pyramidal cells resting on a delicate basement membrane, with stellate myoepithelial (basket) cells scattered between epithelium and basement membrane. The very small alveolar lumina are continuous with intercalated (terminal) tubules that are tributaries of larger interlobular ducts. The intralobular ducts or striated tubules are lined by rodded epithelium composed of low columnar cells with large round centrally located nuclei and characteristic striations in the basal cytoplasm. The interlobular and main excretory ducts are lined with columnar or stratified columnar epithelium except near their openings where the epithelium is stratified squamous, continuous with that of the oral cavity.
The secretory alveoli of the parotid glands are very small (Figures 13-8, 13-30), each consisting of three or four tall pyramidal serous cells arranged eccentrically about the lumen. The relatively large spherical nucleus is near the base of the cell. Below the nucleus the cytoplasm is deeply basophilic; above the nucleus it is more lightly staining and more coarsely granular. The intercalated ducts are short and narrow and are lined by low cuboidal cells with large central nuclei. The septa are delicate and their fibers merge with the loose connective tissue surrounding the lobules.
The secretory alveoli of the submandibular glands are larger, the septa are fibrous, and a fibrous connective tissue capsule surrounds and encloses the lobules. The fibrous septa supporting the large interlobular ducts, blood and lymph vessels, and nerves contain smooth muscle fibers. The alveoli are lined by tall pyramidal serous cells with centrally located nuclei and granular, lightly basophilic, somewhat vacuolated cytoplasm ( Figure 13-30). The intercalated tubules and some of the alveoli have a different structure in adult males from that in females and young males. In adult males the cells are tall columnar and have basally located nuclei and granular vacuolated eosinophilic cytoplasm ( Figure 13-31A). In females and young males the columnar cells are not so tall and the nuclei are centrally located ( Figure 13-31B).
Each sublingual gland is surrounded by a connective tissue capsule and is divided into lobules by projections of the capsule. The secretory mucous cells are tall pyramidal with pale-staining basophilic cytoplasm and basal nuclei ( Figure 13-30). The intercalated ducts are short and narrow and are lined by low cuboidal epithelium. The epithelium of the main excretory duct is stratified columnar.
The digestive tube extends from the pharynx to the anus and includes esophagus, stomach, small intestine, and large intestine. The portion within the body cavity are supported by dorsal mesenteries continuous with the lining of the body cavity, in which blood and lymph vessels and nerves are carried.
The esophagus is a straight tube from the pharynx to the stomach. In the neck region it is dorsal to the larynx and anterior end of the trachea, but as it enters the thoracic cavity it is slightly to the left of the trachea. It traverses the thoracic cavity in a channel between pleural cavities, pierces the diaphragm to the left of center, and enters the stomach in the middle of the lesser curvature.
The stomach is a large dorsoventrally flattened sac located in the left anterior quadrant of the abdominal cavity, partly concealed by the left lateral lobe of the liver. The lesser curvature of the anterior border is short and concave; the greater curvature of the posterior border is long and convex. A division into thin-walled left and thick-walled right portions is visible grossly ( Figure 13-32). The stomach narrows at the right of the lesser curvature where a constriction. the pylorus, marks the boundary between stomach and small intestine.
The small intestine is a coiled tube about 18 inches long, extending from pylorus to cecum and divided into three functionally but not morphologically delimited units, duodenum, jejunum, and ileum. The duodenum consists of a U-shaped loop extending from the pylorus posteriorly to the level of the umbilicus and a transverse portion dorsal to the posterior margin of the stomach. The ileum ends at the cecum, a blind sac in the lower abdominal cavity, and the jejunum is the portion between duodenum and ileum. Elevated and sometimes prominent opaque nodules are scattered in the intestinal wall opposite the mesenteric attachment. These nodules, Peyer's patches, are aggregates of lymphatic tissue and are described with other organs of the lymphatic system.
The large intestine consists of cecum, colon, and rectum. The cecum is an elongated blind sac in the lower abdominal cavity. Its two openings, one from the ileum and one into the colon, are close together. Accumulations of lymphatic tissue are usually visible in the wall near the narrow blind tip. The mouse has no vermiform appendix. The colon is not coiled and consists of an ascending section from cecum to the level of the pylorus, a short transverse section, and a descending section extending posteriorly to the border of the body cavity. The descending colon often appears beaded because of fecal pellets distending its walls. One or more nodules of lymphatic tissue are usually present although not antimesenteric as in the small intestine. The rectum is outside of the body cavity and is a short, thick passageway from the colon to the anus.
The digestive tube has a uniform histological organization throughout its length. The wall is made up of four coats: mucosa, submucosa, muscularis, and either adventitia or serosa. The innermost layer or mucosa consists of the epithelium and associated glands and the lamina propria, composed of reticular and fibroelastic connective tissue supporting blood and lymph vessels and nerves. In some regions the outer boundary of the mucosa is marked by a layer of smooth muscle, the muscularis mucosae. The mucosa is structurally the most varied of the four coats, the epithelial lining being modified for different functions in different portions of the tube. The submucosa is a layer of loose fibrous connective tissue supporting larger vessels and sympathetic neurons and nerve fibers. Glands from the epithelial layer may extend into it. The muscularis is usually arranged as inner circular and outer longitudinal layers of smooth muscle, or striated muscle at the extremities. A sympathetic nerve plexus lies in the connective tissue between the muscle layers. The outermost layer of portions of the tube not within body cavities is the adventitia, a loose fibroelastic connective tissue layer merging with that of adjacent tissues. The covering of portions of the tube within the body cavity is the serosa, loose fibroelastic connective tissue covered by mesothelium (visceral periotoneum) and continuous with the supporting mesenteries and the lining of the body cavity (parietal peritoneum).
The esophagus is lined by stratified squamous cornified epithelium, and the mucosa is in longitudinal folds. There are no glands and no muscularis mucosae. The external muscle coat is striated muscle throughout ( Figure 13-33). The thin-walled left side of the stomach has an epithelium similar to and continuous with that of the esophagus ( Figure 13-34). The thick-walled right side has a much folded glandular epithelium of columnar cells and a muscularis mucosae. The muscularis is in three layers, a thin inner oblique, a wide circular, and a thin outer longitudinal. The circular layer is especially wide at the pylorus.
The two regions of the stomach are separated by a U-shaped ridge around the entrance of the esophagus (the cardiac antrum) with the open ends of the U extending around the body of the stomach ( Figure 13-32). The ridge is formed by thickened lamina propria of the nonglandular stomach. The stomach glands are simple branched tubules, appearing as parallel deep pits perpendicular to the stomach wall. Several short straight tubular glands open into the bottom of each pit. There are three types of gland: cardiac, pyloric, and fundic, the latter being the most numerous. The cardiac glands are adjacent to the ridge and consist of a few tubules made up of columnar cells without secretory granules. The fundic glands are made up of mucous cells, chief or zymogenic cells, and acid-secreting parietal cells. The pyloric glands have deep pits and short gland tubules with mucus-secreting cells. The transition from fundic to pyloric glands is gradual and marked by disappearance of chief and parietal cells.
The surface area of the small intestine is increased by fingerlike projections, the villi. Those of the duodenum are tall and leaf-shaped (Figures 13-35, 13-37; those of the jejunum, tall and cylindrical; those of the ileum, short and cylindrical. The short tubular intestinal glands (crypts of Lieberkühn) open between adjacent villi. Near the pyloris, groups of coiled tubuloalveolar duodenal glands (of Brunner) extend into the submucosa and open into the bases of the intestinal glands ( Figure 13-35). The epithelial cells covering the villi are columnar with oval basal nuclei and striated cuticular borders. Oval goblet cells are scattered among the columnar cells and are especially numerous in the ileum. Other cells, Paneth cells, with acidophilic cytoplasm are found at the bases of the villi, especially in the jejunum. They become conspicuous after several hours of fasting and probably do not represent a unique cell type ( Dunn and Kessel, 1945). The intestinal glands are lined by low columnar and cuboidal cells and the duodenal glands by cuboidal cells.
Vascular lamina propria forms the core of each villus and fills the spaces between glands. Each villus contains a central lymph vessel, the lacteal. Lymphocytes and granular leukocytes are numerous both in the connective tissue and in the epithelium through which they migrate. The solitary lymphatic nodules and aggregated nodules (Peyer's patches) are in the lamina propria and submucosa, interrupting the muscularis mucosae by their presence.
The mucosa of the cecum and of the ascending and transverse colons is in transverse folds, that of the descending colon and rectum in longitudinal folds. The epithelium is composed of columnar cells and many goblet cells ( Figure 13-36A, B). The simple tubular glands become shorter and disappear near the anal opening where the lining of the rectum is cornified squamous epithelium. The muscularis mucosae is poorly developed in the colon and well developed in the rectum ( Figure 13-36A, B). The inner circular layer of the muscularis is very thick and the outer longitudinal layer thin in the rectum, and smooth muscle is replaced by striated muscle near the anal opening. Numerous anal glands of the sebaceous type open into the anal cavity.
With aging the connective tissue of the lamina propria becomes more fibrous and less cellular especially in the duodenum, the villi become shorter and reduced in number, and the mucosa of the large intestine shows signs of atrophy ( Andrew and Andrew, 1957; Suntzeff and Angeletti, 1961).
Gross anatomy. The liver is a large gland occupying the anterior third of the abdominal cavity. The anterior convex surface is pressed against the arch of the diaphragm, and the posterior concave surface fits over and partially conceals the stomach and duodenum. There are four main lobes joined dorsally: the large median subdivided into right and left portions by a deep bifurcation, the undivided left lateral, the right lateral divided horizontally into anterior and posterior portions, and a caudal consisting of two leaf-shaped lobes dorsal and ventral to the esophagus at the lesser curvature of the stomach. Although this is the most frequent pattern of lobation, at least 13 different patterns have been described, the trend being to fission rather than to fusion, and sex and strain differences have been reported ( Rauch, 1952). A characteristic abnormal pattern involving degrees of fusion has been shown to be inherited as a recessive trait ( Bunker, 1959). The adult pattern of lobation takes shape in 15- to 16-day embryos and is greatly influenced by the growth of patterns of the developing gonads ( Danforth and Center, 1953). The liver of the female consistently weighs more than that of the male ( Webster and Liljegren, 1955).
The mouse differs from the rat in having a gall bladder; this is located at the base of the deep bifurcation of the median lobe near the point of origin of the falciform ligament, a membrane continuous with the covering of the liver and with the lining of the body cavity at the median ventral line. The hepatic duct from the liver and the cystic duct from the gall bladder unite to form the common bile duct. This narrow duct extends posteriorly to the duodenum traversing a portion of the pancreas before passing through the intestinal wall to open on a large papilla ( Figure 13-37).
Microscopic anatomy. The surface of the liver is covered by a thin serosa from which fine strands of reticular connective tissue project inward to form the supporting framework for hepatic cells, blood vessels, and bile ducts. Separation into lobules or hepatic units is very indistinct and septa are visible only around interlobular branches of the hepatic artery and hepatic portal vein into sinusoids separating cords of liver cells and converging on a central vein ( Figure 13-38). The sinusoids is endothelium, containing specialized phagocytic cells, the Kupffer cells, which possibly function to insure an even distribution of blood to liver cells.
The hepatic parenchymal cells are large and polygonal with large central nuclei (sometimes two in a cell) and one or more nucleoli. The cell outline is often indistinct and the cytoplasm extremely variable in appearance. It may be granular, vacuolated, deep staining, or very pale. The cells are arranged two deep in cords separated by sinusoids. Bile capillaries are located between the adjoining faces of the cells, the opposite surfaces being in contact with sinusoids. Bile capillaries unite to form bile ducts lined by cuboidal epithelium ( Figure 13-38).
Megakaryocytes are present in the stroma of the liver during the first few weeks of postnatal life and strain differences in the time of their disappearance have been reported ( Fortuyn, 1933). Extramedullary hematopoiesis is seen frequently in adult mice in the reticular tissue of the interlobular septa ( Dunn, 1954).
The mucosa of the gall bladder is folded except when the sac is distended. The lining of cuboidal epithelium is surrounded by a fibroelastic lamina propria, a thin layer of interwoven smooth muscle fibers, and an outer coat which is in part adventitia and in part serosa ( Figure 13-39A). The common bile duct is lined with cuboidal cells changing to columnar where the duct enters the intestinal wall. The walls of the cystic duct and common bile ducts contain a scattering of alveolar glands opening directly into the lumen ( Figure 13-39B).
Gross anatomy. The pancreas is a diffuse pink gland suspended in the mesenteries between stomach, duodenum, and ascending and transverse colons. It extends posteriorly in the duodenal loop, lying close to the mesenteric attachment. It is divided into irregular lobes and lobules. There are several excretory ducts, some joining the bile duct where this traverses the pancreas before entering the duodenum ( Figure 13-40). Usually at least one duct enters the duodenum independently near the entrance of the bile duct.
Microscopic anatomy. The exocrine pancreas is a compound tubuloalveolar gland lacking a connective tissue capsule but surrounded by loose vascular connective tissue of the mesentery and separated into lobes and lobules by septa of loose fibroelastic tissue. The small secretory alveoli, resembling those of the parotid and lacrimal glands, are closely packed and have extremely small lumina ( Figure 13-40). The cells are pyramidal and polyhedral with large round basal nuclei. Around and below the nucleus the cytoplasm is deeply staining and basophilic, whereas above it the cytoplasm is lightly staining, acidophilic, and granular. Variations in cell height, granulation, position of nucleus, and density of stain occur with secretory phases.
The secretion is collected in minute intercalated ducts, lined by very flat cells with elongated nuclei. The interlobular and excretory ducts are lined with cuboidal epithelium and are surrounded by delicate connective tissue supporting vessels and nerves. The endocrine portions, the islets of Langerhans, are always closely associated with the septal ducts and blood vessels ( Figure 13-40).
The respiratory system consists of portions anterior and posterior to the pharynx where respiratory and digestive tracts cross. The air passageways of the anterior division are surrounded by bones of the skull giving the rigidity necessary to prevent collapse at inspiration. The air ducts of the posterior division are supported and given rigidity by cartilaginous plates and rings.
Anterior respiratory tract
This includes nostrils, nasal cavities, and pharyngeal duct (nasopharynx). In addition to functioning as air passageways to the lungs, the nasal cavities are modified for olfaction. For detailed descriptions of the anatomy and histology of the anterior respiratory tract of the mouse and rat see Kelemen ( 1953) and Kelemen and Sargent ( 1946).
Gross anatomy. The nostrils (anterior nares) are small openings on either side of the midline near the tip of the snout. Externally they are guarded by curved folds of thickened skin and internally they communicate through vestibules with the anterior nasal cavities, two narrow lateral chambers separated by a median septum. Two sets of bony ridges, the dorsal and lateral turbinals, decrease the size of each cavity. A long narrow channel from the vestibular region of each anterior cavity leads ventrally and posteriorly to open on the roof of the oral cavity. The median septum extends posteriorly for a short distance and at its end the anterior nasal cavities open through choanae (posterior nares) into the pharyngeal duct, an undivided tubelike structure. The anterior nasal cavities also extend posteriorly into two blindly ending cavities, the ethmoid sinuses, dorsal to the pharyngeal duct. These ethmoid sinuses are separated by a median septum resting on the roof of the pharyngeal duct and are highly developed olfactory organs each containing seven rows of turbinals. The right and left anterior nasal cavities and right and left ethmoid sinuses are in communication through a "window" in the nasal septum just anterior to the choanae ( Kelemen, 1953).
The pharyngeal duct is a straight undivided tube from choanae to pharynx. Its posterior portion is the nasopharynx which is dorsal to the soft palate and communicates through a narrow oval opening with the oropharynx (see the digestive system). There is a narrow oblique slit on either lateral wall of the nasopharynx opening into the Eustachian tube.
Microscopic anatomy. The nostrils, vestibules, and channels to the oral cavity are lined by stratified squamous epithelium. This changes abruptly within the anterior nasal cavities to pseudostratified columnar ciliated with many goblet cells, a type of epithelium that lines most of the respiratory tract. The turbinals of nasal cavities and ethmoid sinuses are covered with olfactory epithelium of pseudostratified columnar type containing specialized bipolar sensory cells. At the posterior border of the soft palate, the epithelium becomes stratified squamous continuous with that of oral cavity and pharynx. The fibrous connective tissue underlying the epithelium merges with the periosteal connective tissue of the skull bones. There are numerous branched alveolar glands with short ducts in the lamina propria of the walls and floor of the anterior nasal cavities and on the roof of the pharynx dorsal and posterior to the rim of the soft palate. The dorsal and ventral portions of the nasal septum are composed of bone, the central portion of cartilage.
Posterior respiratory tract This portion includes larynx, trachea, bronchi, and lungs. The larynx and trachea are embedded in the muscles of the neck region ventral to the esophagus, and the bronchi and lungs are in pleural sacs within the thoracic cavity.
Gross anatomy. The larynx is a chamber with walls partially composed of cartilaginous plates. The anterior end or top of the larynx is on the floor of the pharynx immediately posterior to the base of the tongue, and the opening into it, the glottis, is a slit between dorsoventral folds (the vocal cords) projecting from its lateral walls. A triangular flap of tissue, the epiglottis, projects from the anteroventral border into the pharynx. When the larynx is raised in the act of swallowing, its top and the epiglottis fit into the nasopharynx preventing the entrance of swallowed material into the air passages. The ventral wall contains the large shield-shaped thyroid cartilage to which the epiglottis is attached. The cricoid cartilage, which encircles the larynx posterior to the thyroid cartilage, is wider on the dorsal than ventral side. The paired arytenoid cartilages support the dorsal rim of the glottis and extend ventrally into the vocal cords.
The trachea extends from the narrowed end of the larynx into the thoracic cavity where it branches dorsal to the aortic arch into left and right bronchi. The tracheal walls are stiffened by cartilage rings that are incomplete dorsally, leaving a flexible strip in the wall adjacent to the esophagus. The rings, especially the most anterior ones, are uneven, branching and fusing with one another. The large primary bronchi, completely encircled by irregular cartilage plates, lead into the right and left lungs where further divisions take place. There are no cartilages in the walls of bronchi within the lungs.
The lungs are divided into lobes, the normal pattern being a single lobe on the left and four on the right: three in a row (anterior, middle, and posterior); and one (the median, cardiac, or infracardiac lobe) against the diaphragm to the left of the midline. This pattern of lobation was the most frequent of nine patterns observed in a study of eight strains ( Browder, 1942). The lungs are covered by a serous membrane, the visceral or pulmonary pleura, and are suspended within pleural cavities lined by parietal pleura. The medial walls of the two pleural cavities meet anterior and posterior to pericardial cavity to form the double-walled mediastinal septum. The left lung lobe lies in the left pleural cavity, three of the right lobes lie in the right cavity, and the median lobe lies in a fold of the mediastinal septum to the left of the inferior vena cava.
Microscopic anatomy. The lingual surface of the epiglottis and the anterior surface of the vocal cords are covered by stratified squamous epithelium. The remainder of the larynx, trachea, and larger bronchi are lined by pseudostratified columnar ciliated (respiratory) epithelium with many goblet cells. The lamina propria of all regions is fibroelastic connective tissue supporting numerous alveolar glands in the larynx and anterior end of the trachea. Some of the alveoli are composed of serous and some of mucous cells, and their short ducts are lined by ciliated cuboidal cells. There are no subepithelial glands on the epiglottis, vocal cords, posterior portion of the trachea, bronchi, or smaller respiratory tubes. The lamina propria merges with the dense fibrous perichondrium of the pharyngeal, tracheal, and bronchial cartilages. The cartilages are hyalin except for those of the epiglottis and arytenoids in which there are elastic and reticular fibers. The cartilages of the larynx are connected with each other and to adjacent structures by strands of fibrous connective tissue and bundles of striated muscle. The open ends of the tracheal rings are joined by the smooth muscles attached to the dorsal surface of the perichondrium. When the muscle is contracted, the mucous membrane in this region is thrown into longitudinal folds. There are no muscle layers surrounding either larynx or trachea; the connective tissue adventitia anchors them to surrounding muscles of bone. The primary bronchi resemble the posterior portion of the trachea in structure except for having cartilage in the dorsal wall, a layer of smooth muscle, and serosa (visceral pleura).
The bronchi branch repeatedly after entering the lung, diminishing in size with each division. The secondary and tertiary bronchi resemble the primary bronchi except that their walls lack cartilage and serosa. The smaller bronchi are lined by simple columnar ciliated cells and the bronchioles by low columnar epithelium lacking both cilia and goblet cells. As the tubes become smaller their walls become thinner and contain less connective tissue and smooth muscle. The terminal bronchioles give rise to respiratory bronchioles, each branching into several alveolar ducts and alveolar ducts lead into alveolar sacs, each composed of several alveoli ( Figure 13-41). Terminal and respiratory bronchioles are lined with cuboidal epithelial cells surrounded by thin connective tissue sheets containing scattered smooth muscle cells. The cuboidal epithelium ends abruptly at the junctions of respiratory bronchioles and alveolar ducts where it is replaced by squamous epithelium. Alveolar ducts, alveolar sacs, and alveoli have very thin walls invested with fine close-meshed networks of large thin-walled capillaries. Electron microscopic studies of the structure of alveoli and pulmonary capillaries have shown that both alveolar epithelium and capillary endothelium are continuous uninterrupted layers with a thin, structureless basement membrane between them ( Low, 1953; Karrer, 1956). Two types of alveolar epithelial cells have been described: one with its thick nucleus-containing portion protruding into the alveolar lumen, and the other often in a niche of the alveolar wall ( Karrer, 1956). Free macrophages, usually in contact with the alveolar epithelium adjacent to an alveolar septum, were seen in small numbers in all lungs studied ( Karrer, 1958). Alveoli are separated from alveolar sacs by interlobular connective tissue supporting arteries and veins.
The lungs receive blood from two sources: aerated blood through bronchial arteries from the systemic circulation, and venous blood through the pulmonary arteries from the heart. The pulmonary arteries and veins follow the bronchi, and the very thin capillaries invest the alveolar walls. The walls of the pulmonary veins contain cardiac muscle ( Figure 13-41).
The urinary system includes kidneys, ureters, urinary bladder, and urethra.
Gross anatomy. The kidneys are paired bean-shaped organs lying retroperitoneally against the dorsal body wall on either side of the vertebral column. They are not attached to the body wall, but are held loosely in place by adipose tissue. The right kidney is larger, heavier, and located more anteriorly. The anterior pole of the right kidney is usually at the level of the 12th rib, that of the left kidney at the level of the 13th or just posterior to it. There is a sex difference, the male kidney being consistently heavier and larger throughout life. The shape and size of the kidney varies somewhat with strain of mice; in strain C58, 10 to 12 per cent of animals have one or both kidneys reduced in size or missing ( Hummel, 1954).
The kidney is dorsoventrally flattened and has an extensive convex lateral and a short concave medial border. The concavity is the hilus where blood vessels and the ureter join the kidney. Two layers, cortex and medulla, can be seen without the aid of a lens if the kidney is bisected. The cortex follows the contours of the convex border, and the medulla is like a broad pyramid with its convex base fitted against the concave surface of the cortex. The apex of the pyramid is the papilla which is surrounded by the pelvis, the expanded funnel-like anterior end of the ureter.
Development of the kidney, ureter, and associated blood vessels has been described by Brown ( 1931) and Carter ( 1954).
Microscopic anatomy. The kidney is composed of units or nephrons held together by delicate, richly vascular connective tissue strands and enclosed in a thin connective tissue capsule. The ventral surface is covered by peritoneum. Each nephron is a tubule with a widened end, Bowman's capsule, enclosed a tuft of blood capillaries, the glomerulus. The tubule consists of proximal and distal convoluted portions with a straight segment, Henle's loop, between. The nephrons drain into straight collecting tubules that join others to form large tubules opening into the pelvis near the tip of the papilla. The nephron is structurally similar to that of man, as is the blood-vessel architecture. For histological details of each region and for the arrangement of arteries, veins, and capillaries see a histology text.
The outer zone of the cortex is composed predominantly of glomeruli and convoluted tubes ( Figure 13-42). The straight tubules of Henle's loops are grouped into bundles and give a rayed appearance to the inner zone of the cortex. The medulla has a striated appearance, being composed chiefly of straight collecting tubules converging toward the papilla.
Certain features of the mouse kidney are noteworthy. Compared to male animals of many species, the mouse has a glomerular volume (number and size) of about one-half of that predicted on the basis of kidney size and volume ( Rytand, 1938). The granular cells in the walls of the afferent glomerular arteries (the juxtaglomerular apparatus) are easily demonstrated in the mouse, in contrast to the difficulties of revealing them in man ( Dunn, 1949a). There is a sex difference in the relative number of Bowman's capsules that have parietal linings of cuboidal rather than squamous cells. Most of the parietal epithelium in females and young and castrated males is the squamous type found in kidneys of moist other animals, whereas many of the Bowman's capsules of the adult male are lined by cuboidal cells ( Crabtree, 1941).
Gross anatomy. The ureter extends from the kidney to the urinary bladder passing dorsal to uterine horn and vas deferens. The widened anterior end, the pelvis, is surrounded by kidney cortex. The ureters enter the dorsal wall of the neck of the bladder separately, lateral to the entrances of the vasa deferentia in the male. An intramural part courses through the bladder muscles in a slightly oblique direction, serving as a barrier to reverse movements of urine.
Microscopic anatomy. The epithelium of the pelvis is contiguous with that covering the papilla and lining the ducts of the larger collecting tubules, as well as with that lining the rest of the ureter. The wall of the pelvis is composed of a thin layer of transitional epithelium surrounded by layers of fibrous connective tissue and loose connective tissue containing adipose cells. The epithelium covering the papilla is transitional in deeper regions and usually simple low columnar to cuboidal over the tip and lining the collecting ducts ( Figure 13-42). The wall of the ureter is composed of transitional epithelium, a fibrous lamina propria, an inner circular and an outer longitudinal layer of smooth muscle fibers, and an adventitia of loose connective tissue and adipose cells ( Figure 13-43). The mucosa is in low longitudinal folds.
Gross anatomy. The pear-shaped bladder is in the posterior abdominal cavity in the midline of the body ventral to the colon. It varies in size with the amount of urine contained. posteriorly it narrows into a neck continuous with the urethra. The bladder is attached to the ventral body wall by the ventral ligament.
Microscopic anatomy. The bladder is lined by transitional epithelium consisting of two to four layers of cells when the bladder is empty and one or two layers when distended. The fibrous lamina propria is richly vascular, occasionally containing aggregations of lymphocytes. In the empty bladder the mucosa is thrown into wide irregular folds (Figure 13-44) which disappear in the distended organ. The muscularis is wide and consists of smooth muscle bundles of irregular size and direction separated by considerable amounts of connective tissue. Around the neck of the bladder, the muscle bundles are circularly arranged to form a sphincter. The adventitia is fibroelastic tissue covered in part by a serous membrane continuous with the ventral ligament and elsewhere merging with adjacent loose connective tissue.
Gross anatomy. The female urethra is a short tube, slightly flattened dorsoventrally, extending from the neck of the bladder to an external opening in the clitoral fossa, a depression near the tip of the clitoris just anterior to the vaginal orifice. The male urethra, modified to function as a duct for both urine and male sex cells, is described under the male genital system.
Microscopic anatomy. The mucous membrane is in longitudinal folds, the epithelium is transitional, and the lamina propria is dense fibrous connective tissue supporting numerous blood vessels. Alveolar urethral glands, with short ducts opening directly into the lumen, are present in the connective tissue posterior to the neck of the bladder on ventral and lateral sides only. At the neck of the bladder, the smooth muscle layers continuous with the musculature of the bladder are replaced by striated muscle forming an especially thick circular coat on the ventral side. A loose connective tissue adventitia surrounds the muscle layers and merges with adjacent structures. Near the external orifice, the urethra passes through the clitoris where the structure of the urethral wall is modified ( Figure 13-62). The clitoris is described with the female genital system.
MALE GENITAL SYSTEM
The male genital system consists of testes, excretory ducts, accessory glands, and urethra and penis ( Figure 13-45).
Gross anatomy. The paired testes are located in the posterior body cavity on either side of the urinary bladder or in the scrotal sacs. The scrotal sacs are extensions of the body cavity into the subcutaneous tissue on either side of the penial urethra, just anterior to the anus and base of the tail. Their cavities remain in communication with the body cavity through inguinal canals that remain open throughout life, and the testes are often in a retracted position. The fat body attached to the epididymus occupies the inguinal canal when the testis is in the scrotal sac.
The testis is an oval body, consisting of coiled tubules held together by connective tissue and covered by a tough membrane, the tunica albuginea. In a mature male, the testis weighs about 85 mg, and measures 8.5 x 5 x 5 mm. The total tubule length has been estimated at between 1.7 and 2 m ( Bascom and Osterud, 1925). The testis has exocrine and endocrine functions; mature sex cells, spermatozoa, are produced in the testis and discharged into the excretory ducts; and male hormones, the androgens, are excreted directly into the blood stream. The sex cells mature in the walls of the tubules, and the endocrine cells are scattered in the intertubular connective tissue.
Microscopic anatomy. The tunica albuginea or capsule of the testis is a thick layer of fibrous connective tissue with a covering of mesothelial cells. Thin septa with blood vessels project into the gland and divide it into irregular lobules. The lobules contain the convoluted seminiferous tubules and the richly vascular intertubular stroma with groups of interstitial (Leydig) cells. The tubules are made up of specialized seminiferous epithelium resting on a basement membrane and covered by thin connective tissue merging with the intertubular stroma. The seminiferous epithelium contains two kinds of cells: sustentacular Sertoli cells, and male sex cells undergoing spermatogenesis and spermiogenesis. For details of these processes, see Chapter 7 and Chapter 11.
The Sertoli cells are spaced at fairly regular intervals against the basement membrane; they have indistinct outlines and large oval often indented nuclei with compound nucleoli consisting of one central acidophilic and two peripheral basophilic bodies. When a Sertoli cell is fulfilling its normal function of supporting spermatozoa, it is pyramidal in shape with the apex directed toward the lumen and the nucleus perpendicular to the tubule wall; when resting, the cell is polygonal and the nucleus is parallel to the wall. Under certain abnormal conditions, which result in degeneration or atrophy of the seminiferous cells, the tubules are lined with the more resistant Sertoli cells.
The spermatogenic cells are arranged in layers that vary in number with phase of spermatogenic activity; this process does not take place simultaneously in all tubules. The most primitive sex cells are the spermatogonia, resting on the basement membrane and interrupted at intervals by Sertoli cells. Cells of the outer layers are those resulting from divisions of the spermatogonia: the spermatocytes, spermatids, and immature spermatozoa. Spermatids are small spherical cells that remain in close association with Sertoli cells during their transformation into spermatozoa. The heads of immature spermatozoa are buried in Sertoli cells, and the tails extend into the lumen. The fully mature spermatozoa become free of the sustentacular cells, pass into the lumen, and thence into excretory ducts.
A mature spermatozoon, found in the lumina of testis tubules and excretory ducts, is made up of head, middle piece, and tail. The head is sickle-shaped and flattened, and the tail long and flagellate. There are strain differences in the breadth and length of the head, the shape of the posterior end of the head, the shape of the posterior end of the head, and the shape of the middle piece ( Braden, 1958; Sharma, 1960).
The interstitial cells, which secrete androgenic hormones, are in irregularly sized groups in the intertubular loose connective tissue in close association with capillaries. The cells are small with indistinct cell outlines, acidophilic cytoplasm, and large nuclei containing one or two nucleoli and coarse chromatin granules.
Gross anatomy. The excretory ducts include the rete, the efferent ducts, the epididymus, and the ductus (vas) deferens (Figures 13-45, 13-46). Near the hilus of the testis within the tunica, the tubules become straight and are gathered into a network, the rete, from which three to five efferent ducts emerge. The efferent ducts pierce the tunica and become enclosed within the capsule of the epididymus where they unite to form a single duct, the duct of the epididymis. The epididymus consists of three regions, caput, corpus, and cauda ( Figure 13-46). In the caput and corpus, the duct is extremely convoluted, but less so in the cauda. The ductus deferens is a straight tubule extending from the cauda to the urethra, passing ventral to the ureter and widening into an ampulla before entering the dorsal wall of the urethra near the neck of the bladder. The ductus deferens and closely associated blood vessels and nerves make up the spermatic cord.
Microscopic anatomy. In the hilus region of the testis where the convoluted tubules transform into straight tubules, the epithelial lining is low columnar; in the irregular spaces of the rete it is low cuboidal or squamous. The efferent ducts are lined by alternating groups of tall and low columnar cells, giving the lumen a characteristic scalloped outline ( Figure 13-48). Basement membranes and a few circularly arranged smooth muscle fibers complete the duct walls. loose connective tissue fills the spaces between ducts and the composite is surrounded by a fibrous connective tissue capsule continuous with that of the epididymus.
The epididymis is covered throughout its length by a fibrous connective tissue sheath which projects into the caput and divides it into seven or eight segments or lobules ( Figure 13-47). The first of these segments contains portions of the efferent duct and the others contain the very coiled duct of the epididymis. This duct is lined by columnar or cuboidal cells bearing tufts of large nonmotile stereocilia on their free surfaces ( Figure 13-48). Secretion granules are visible in the cytoplasm between the free margins and the basal nuclei, and excretion takes place in the cytoplasmic extensions between stereocilia. The lumen is wide in the first and second segments, is narrowed in the third and subsequent segments, and again becomes wider toward the cauda. In the second segment the epithelial cells are very tall and not all of their nuclei are basal. In the third and subsequent segments of the caput and in the corpus and cauda, the epithelium is made up of a single layer of low columnar cells with centrally located nuclei. There is a layer of small round cells between the epithelium and the basement membrane throughout and, surrounding these, one or two layers of circularly arranged smooth muscle fibers.
The mucosa of the ductus deferens, consisting of columnar epithelium and a delicate fibrous lamina propria, projects into the lumen in tall, regularly spaced longitudinal folds and short, irregular circular elevations. The tall columnar cells have tufts of stereocilia on their free surfaces, oval centrally located nuclei, and light-staining cytoplasm with secretion granules ( Figure 13-49). Between the mucosal folds the epithelium appears to be pseudostratified and, as in the epididymis, flat cells with small densely staining nuclei lie between the epithelial cells and the basement membrane. In the ampulla, the epithelium changes abruptly to low columnar without stereocilia, and the mucosa is in tall irregular folds. The fibrous lamina propria is very thin and is surrounded by a wide layer of circularly arranged smooth muscle fibers and a much thinner layer of longitudinal fibers ( Figure 13-49). The serosa is thin except at the point of the mesotubarium attachment, where the fibrous tissue supports the vessels and nerves that accompany the duct in the spermatic cord.
Urethra and penis
Gross anatomy. The male urethra is a long duct extending from the urinary bladder to an opening on the tip of the penis. The portion of the urethra from the neck of the bladder to the pelvic girdle has a relatively thin wall and is referred to as the membranous urethra. The penial urethra is surrounded by the erectile, muscular, and fibrous tissues of the penis.
The urethra enters the penis at the posterior border of the pelvic girdle, where a bulbous diverticulum extends laterally and posteriorly. From this point the penis extends anteriorly along the ventral wall within the subcutaneous tissue to terminate on the ventrally elevated genital papilla. The external orifice of the urethra is at the tip of the glans, the club-shaped terminal end of the penis, which is covered by a reflected fold of skin, the prepuce or foreskin. A small bone, the os penis, projects slightly beyond the orifice.
The body of the penis is made up of three masses of erectile tissue (corpus cavernosum urethrae and two corpora cavernosa penis) within heavy connective tissue membranes that also serve to attach the penis to the pelvic girdle. The thin cavernosum urethrae, which is ventral to the urethra, expands proximally over the urethral diverticulum or bulb and extends distally a short distance between the heavier corpora cavernosa penis. The corpora cavernosa penis extend laterally and dorsally and almost encircle the urethra. These are separated proximally by individual coverings but are a single mass distally. At the region of the urethral diverticulum, the two corpora diverge and their tunicas merge with the connective tissues of the bulbocavernosus muscle that covers the urethral diverticulum and the ischiocavernosus muscle that inserts on the ischium. Distally the corpora cavernosa penis extend to the glans.
Microscopic anatomy. The membranous urethra is lined by transitional epithelium except over the colliculus seminalis on the dorsal wall at the neck of the bladder. This elevation is covered by low columnar epithelium, a continuation of that of the ducts of the ampullary and vesicular glands. The richly vascular lamina propria supports the urethral glands of Littré, which form a complete sheath around the urethra from the neck of the bladder to the junction with the penis ( Figure 13-51). These glands are groups of alveoli made up of secretory cells with oval basal nuclei and cytoplasm containing basophilic secretion granules. Their short ducts, lined by cuboidal epithelium, open separately into the lumen. A thick layer of striated muscle surrounds the gland layer, this in turn being surrounded by connective tissue merging with that of adjacent structures.
The urethral diverticulum is lined also with transitional epithelium, its thickness depending on dilatation and the amount of secretion present. Glands similar to those in the membranous urethral wall open directly into the lumen by short ducts. The diverticulum is partially surrounded by an extension of the corpus cavernosus urethrae and its membrane composed of an inner circularly arranged smooth-muscle sheath and an outer sheath of fibrous connective tissue. Trabeculae from this muscular and fibrous membrane penetrate among the glands to form cavernous spaces lined with endothelium. When the spaces are distended with blood, groups of glands are widely separated; when the spaces are collapsed, the glandular tissue appears compact. The connective tissue of the outer sheath merges with the perimysium of the bulbocavernosus and ischiocavernosus muscles, which are composed of thick bundles of striated muscle.
Transitional epithelium lines the urethra from the diverticulum to near the tip of the penis, where it changes to stratified squamous at the orifice. Glands are absent and the fibrous lamina propria is continuous with the surrounding cavernous spaces of the corpora cavernosa penis. In the proximal penis, each corpus is surrounded by a tunica, but distally these disappear except for a narrow septum, and the cavernous spaces intercommunicate. The os penis is located in the connective tissue of the septum.
The glans is covered and the preputial cavity lined with hairless skin. Over the glans, the epidermis projects deeply into the dermis and cornified filiform papillae project from the pits thus formed ( Figure 13-50). A very vascular dermis fills the narrow spaces between the epidermal invaginations, and the subcutaneous connective tissue merges with that surrounding os penis and urethra. The epidermis of the prepuce has a thick surface layer of noncornified squamous cells and a width varied by the dermal papillae that project into it at frequent intervals ( Figure 13-50). The fibrous subcutaneous tissue contains smooth muscle fibers.
Gross anatomy. The neck of the bladder and the anterior end of the urethra are surrounded by accessory glands and their ducts (Figures 13-45, 13-51). The largest and most prominent are the paired, elongated, curved vesicular glands (the seminal vesicles of older literature), which are separated medially and hooked at the narrowed tips. Each vesicular gland has a wide duct that enters the urethra with the ampulla of the vas deferens on an elevation, the colliculus seminalis, located on the dorsal wall of the urethra near the neck of the bladder ( Figure 13-51). Infrequently, the vas deferens and vesicular-gland duct join on one or both sides before entering the urethra.
The paired coagulating glands are attached to the lesser curvatures of the vesicular glands. They are less prominent and less opaque than the vesicular glands and their much folded mucosa is visible through the skin, somewhat transparent, walls. Each gland has two ducts entering the dorsal wall of the neck of the bladder anterior to the colliculus seminalis ( Figure 13-51).
The ampullary glands are groups of branched tubular glands with many short ducts that open directly into the wide vestibules of the ampullae ( Figure 13-51).
The dorsal and ventral prostates are the other glands of this region. The dorsal prostate has many ducts, some entering the urethra lateral to all other ducts. The ventral prostate has several ducts entering the ventral walls of the urethra.
The bulbourethral (Cowper's) glands are paired structures lateral to the junction of the membranous urethra and penis. The main body of the gland is at the side of the urethral diverticulum buried in the bulbocavernosus muscle, the tail is between the diverticulum and the ischiocavernosus muscle, and the duct enters the urethra immediately anterior to the diverticulum ( Figure 13-45).
The preputial glands are large dorsoventrally flattened leaf-shaped glands lying close together in the subcutaneous tissue near the end of the penis. Their ducts empty into the lateral wall of the preputial cavity.
Microscopic anatomy. The ampullary glands are groups of branched tubules lined by low columnar cells with large oval nuclei. The lamina propria is very thin and the mucous membrane is thrown into many deep longitudinal folds. The tubules are surrounded by a very thin layer of smooth muscle cells and are held together by a thin connective tissue membrane. In eosin-stained sections the secretion is deep red and homogeneous and tends to shrink away from the epithelial lining.
The vesicular gland has a large elongated internal cavity with medial alveolar outpocketings. The mucosa, especially on the medial side, is thrown into many fine intricate folds. The epithelium consists of tall columnar cells with distinct boundaries and large oval basal nuclei. The slightly basophilic cytoplasm contains dark secretion granules surrounded by lighter staining areas or halos. When the lumen is distended by secretion, the epithelial cells are low columnar and do not contain secretion granules. Smooth muscle fibers and a connective tissue sheath surround the gland. The secretion is intensely acidophilic in prepared sections and tends to appear as though cracked into parallel fissures.
The mucous membrane of the coagulating glands forms curved longitudinal folds, some projecting far into the lumen. The epithelium consists of a layer of columnar cells with round centrally located nuclei and acidophilic cytoplasm. Each gland usually has two ducts lined by low columnar cells with deeply staining nuclei and slightly basophilic cytoplasm. The ducts have a folded mucosa giving the lumen a wavy outline. The gland tubules are surrounded by a delicate layer of smooth muscle fibers, and the mass of tubules is contained within a connective tissue sheath which attaches it to the vesicular gland. The secretion is a homogeneous faintly acidophilic substance appearing cracked in stained sections.
The tubules of the dorsal prostate glands are structurally similar to those of the coagulating glands, although considerably narrower. The mucous membrane is folded in the secretory tubules but not in the ducts. The secretion also is similar to that of the coagulating gland except that "cracking" is rare. The gland tubules of the ventral prostate are lined by low columnar cells with spherical deeply staining nuclei and slightly basophilic cytoplasm. The mucosa is folded in inactive but not in distended tubules. The gland tubules have thin coats of smooth muscle and are held together and surrounded by a fibrous sheath. The secretion is slightly acidophilic and tends to mass into globules of varying size.
The bulbourethral gland is composed of body and tail. The body is partially covered by the bulbocavernosus muscle and the tail is surrounded by the ischiocavernosus muscle. A thin connective tissue membrane projects into the gland separating the alveoli and supporting the blood vessels. The tubules and alveoli of the body of the gland are lined by tall columnar cells of uneven height. The granular cytoplasm is slightly basophilic and very light staining, and the nuclei are small, darkly staining, and flattened against the cell bases. The basement membrane is well developed. The alveoli of the tail portion are lined by low columnar cells with granular dark-staining basophilic cytoplasm and round basal nuclei. Interspersed among these cells are small groups of more lightly staining cells similar to those of the body of the gland. The ducts of body and tail are lined by cuboidal epithelium.
The preputial glands are large sebaceous glands made up of groups of flat polyhedral cells with pale-staining nuclei, surrounded by a connective tissue capsule ( Figure 13-52). In an actively secreting cell, the major portion is filled with an oily secretion, and when the nucleus degenerates the dead secretion-packed cell is excreted. Each gland has a long duct lined with stratified squamous epithelium opening into the preputial cavity. Near the orifice the epithelial cells of the duct and the subcutaneous tissue around it usually contain some pigment (except in albino animals).
FEMALE GENITAL SYSTEM
The female genital system is composed of ovaries, oviducts, uterus, and vagina ( Figure 13-53). For a detailed description of the anatomy and development of ovary, oviduct, and uterus see Agduhr ( 1927).
Gross anatomy. The ovaries are small paired spherical bodies functioning to produce mature female sex cells (ova) and sex hormones. They are located at the posterolateral poles of the kidneys, each attached by the mesovarium to the dorsal body wall and enclosed in a thin transparent elastic capsule or bursa. The periovarian space is shut off from the abdominal cavity except for a tiny tunnel-like channel through the bursa ( Wimsatt and Waldo, 1945). Blood vessels and nerves supported in the mesovarium enter and leave the ovary through a stalk at the hilus where the periovarian space is interrupted. The surface of the ovary is smooth in prepuberal females but becomes nodular after sexual maturity because of the presence of follicles and corpora lutea. Conspicuous strain and age differences in ovarian size are largely the result of differences in numbers of follicles and corpora lutea (Fekete, 1946, 1953).
Microscopic anatomy. The capsule is a thin membrane composed of loose connective tissue, blood vessels, nerves and a few smooth muscle fibers covered on inner and outer surfaces by mesothelium. Near the hilus of the ovary, adipose tissue is accumulated between the mesothelial layers to form the fat body ( Figure 13-54). The surface of the ovary is covered with a layer of cuboidal cells with large nuclei, small amounts of cytoplasm, and slightly rounded free surfaces. This "germinal" epithelium rests on a prominent basement membrane and follows the contours of the ovary, being thinner where follicles and corpora lutea bulge the surface ( Figure 13-56).
Two poorly defined areas, a central vascular medulla and a compact outer cortex, are visible in sections ( Figure 13-54). The large blood vessels that join the ovary at its hilus branch in the dense fibrous connective tissue stroma of the central medullary portion. Rudiments of the rete ovarii may persist in the medulla near the hilus as blind tubules or cords of epithelial cells, and cysts with this derivation are especially large and numerous in the ovaries of C57L mice ( Fekete, 1953). Other mesonephric remnants may persist as the epoophoron, a small mass of cells in the mesovarium. The cortex is composed of strands of loose fibrous stroma separating developing follicles and corpora lutea and supporting groups of interstitial cells and blood vessels. The primordial follicles, consisting of single layers of flat cells surrounding oocytes, are massed beneath the germinal epithelium in the tunica albuginea ( Figure 13-55). The oocyte or ovum is a clear spherical cell with a vesicular nucleus containing small chromatin granules and a prominent nucleolus. Although a follicle usually contains a single ovum, polyovular follicles are not uncommon in young mice ( Kent, 1960) and follicles with two to five ova are numerous in ovaries of strain C58 mice ( Fekete, 1950). The number of primordial follicles is gradually depleted by ovulation and atresia, and the tunica albuginea in the senile ovary is dense and conspicuous. Depletion of follicles and oocytes proceeds at different rates in mice of different strains ( Jones and Krohn, 1961).
During maturation, which occurs simultaneously in several follicles, both oocyte and follicle enlarge, and the single layer of flat cells is replaced by a many-layered stratum granulosum, made up of small basophilic follicular or granulosa cells. As the follicle grows larger it moves centrally and acquires a liquor-filled cavity or antrum and an encapsulating sheath derived from stromal cells. Later two layers, a vascular theca interna and a fibrous theca externa differentiate in the sheath. Blood and lymph vessels penetrate the externa to form a plexus in the interna, but the granulosa layer is avascular. The oocyte loses its direct connection with granulosa cells through deposition around it of a zone of acellular material, the zona pellucida. A mature (Graafian) follicle bulges into the periovarian space, separated from it by the stretched theca and germinal epithelium. The oocyte and first polar body surrounded by the zona pellucida and a cluster of follicle cells, the cumulus oophorus, retains a slim attachment to the thinning granulosa layers. The theca interna cells are hypertrophied and vacuolated. At ovulation, the germinal epithelium ruptures and the oocyte with its cluster of cells is released into the periovarian space. For a discussion of the processes of oogenesis and ovulation see Chapters 7, 11.
Immediately on release of ova, the follicles begin to change into corpora lutea ( Figure 13-56). The ruptured epithelium heals, granulosa cells hypertrophy, and connective tissue and capillaries grow inward from the theca interna, obliterating the antrum. The granulosa cell of the mature follicle is small and basophilic with a large oval nucleus, whereas the mature lutein cell that develops from it is large with clear vacuolated eosinophilic cytoplasm and a large vesicular nucleus. Several follicles mature at each estrus, so several generations of corpora lutea may be present in an active ovary. The cells of newly formed corpora are small and slightly basophilic, and those of older bodies are large and eosinophilic and are arranged in cords around branching sinusoids. Many of the ova and follicles do not mature but undergo atresia during one or another stage of development. Atretic follicles with pycnotic cells, fragmented ova, and remnants of zona pellucida are scattered throughout the cortical stroma.
The interstitial cells are similar morphologically to mature lutein cells and are found in irregular groups among the fibrous stromal cells. Their origin is in doubt and they may derive from several sources: hypertrophied stromal cells, remnants of corpora lutea, and theca interna cells ( Figure 13-56. The interstitial cells are believed to be a source of androgens as well as of estrogens; other secretory cells of the ovary are those of corpus luteum and theca interna and possibly granulosa cells. In ovaries of old mice large cells containing a brown pigment are frequent components, their number, size, and clumping patterns being strain characteristics ( Fekete, 1946, 1953). Histological observations indicate that the pigment is identical to that occurring in cells of aged adrenals ( Deane and Fawcett, 1952).
Gross anatomy. The oviduct (uterine or fallopian tube) is a long (1.8 cm) narrow coiled tube connecting the periovarian space with the uterine horn. It is suspended from the dorsal body wall by the mesotubarium, a double-walled membrane continuous with mesovarium, ovarian bursa, and the mesometrium of the uterus. There are three segments of oviduct: the widened ampulla near the ovarian bursa; the long, narrow, tightly coiled isthmus; and the internal portion within the uterine wall. The ampulla opens through an infundibulum into the periovarian space. Fringe-like processes, the fimbriae, surround the opening and extend into the periovarian space ( Figure 13-54). The oviduct joins the uterus on its dorsolateral wall slightly posterior to its rounded anterior end, passes obliquely through the wall, and opens at the tip of a projection, the colliculus tubarius. Kuhlmann (1965, personal communication) describes the colliculus as a projection varying in length from 0.2 to 0.6 mm surrounded at the base by a furrow and with circular folds in its wall. He finds strain differences in the depth of the furrow, the number of folds, and the shape and length of the projection. In strain BALB/c females the colliculus is mound-shaped with a normal length of about 0.3 mm, whereas in strain 129 females, it is cylindrical or conical, has two or more encircling folds, and has a normal length of 0.4 mm; in abnormal situations the colliculus may exceed 1 mm in length.
Microscopic anatomy. The mucosa is elaborately folded in the ampulla of the oviduct and is in four to six longitudinal folds in the intramural and colliculus tubarius portions. The amount and direction of folding varies in different portions of the isthmus ( Agduhr, 1927). The epithelium lining the ampulla and infundibulum and covering the fimbriae is ciliated columnar ( Figure 13-57). The cells are tall with oval centrally located nuclei, eosinophilic cytoplasm, and long motile cilia. Scattered among these cells are club-shaped nonciliated cells protruding into the lumen. The isthmus is lined with pseudostratified and low columnar epithelium containing an occasional ciliated cell ( Figure 13-58), and the intramural portion is lined with simple columnar epithelium. The lamina propria consists of a thin layer of connective tissue containing a few elastic and smooth muscle fibers. The muscularis, of circularly arranged smooth muscle fibers, is thin in the isthmus and becomes progressively thicker distally. In the intramural and colliculus tubarius portions, the muscularis of the oviduct merges with the circular muscle layer of the uterine wall ( Figure 13-59).
Gross anatomy. The uterus is a Y-shaped tubular structure divided into two lateral horns (cornua) and a single median body (corpus) ( Figure 13-53). The uterine horns extend posteromedially from the oviducts to a position dorsal to the urinary bladder where they unite to form the corpus. The horns are suspended from the dorsal body wall by the heavy broad ligaments or mesometria through which blood and lymph vessels and nerves course at regular intervals. The body of the uterus consists of a cranial portion, containing two cavities separated by a median septum, and a caudal undivided portion, the neck or cervix, projecting into the cavity of the vagina ( Figure 13-53). The walls of the cervix and vagina are continuous dorsally and ventrally but not laterally where the lumen of the vagina extends anteriorly into deep fornices. In the rat the median septum extends the length of the corpus and the two lateral chambers open separately into the vaginal lumen.
Microscopic anatomy. The mucosa of the uterine horns, called the endometrium in nonpregnant females, is elevated into transverse folds and is well supplied with blood vessels and nerves ( Figure 13-60). The epithelium is simple columnar extended into branched tubular glands projecting into the endometrial stroma, which is composed of reticular tissue containing many small polyhedral cells and many lymphocytes. The muscle layer, or myometrium, consists of inner circular and outer longitudinal layers of smooth muscle with a layer of very vascular loose connective tissue, the stratum vasculosum, between. The outer covering is serosa continuous with the mesometrium.
As the uterine horns come together in the midline, their medial walls lose serosa, stratum vasculosum, and some muscle fibers and fuse to form a partition that extends through the lumen almost to the level of the vaginal fornices. Some circular muscle fibers are retained in the center of the partition ( Figure 13-61A). The lateral cavities are lined with epithelium that changes gradually from simple columnar to stratified squamous. The most anterior portions of the corpus are lined entirely by epithelium similar to that of uterine horns, but elsewhere, especially on the medial walls, patches of stratified squamous epithelium are interspersed ( Figure 13-61A). The undivided cavity of the corpus ( Figure 13-61B) and the cervical canal are lined by stratified squamous epithelium continuous with that of the vagina. The lamina propria of the uterine corpus is less cellular and more fibrous than that of the horns. Circular and longitudinal smooth muscle fibers and serosa complete the wall. The wall of the cranial two-thirds of the cervix contains circularly arranged smooth muscle; the wall of the caudal one-third contains collagenous fiber bundles that become loose and widely separated during pregnancy ( Leppi, 1964).
Vagina and clitoris
Gross anatomy. The short, thick, muscular vagina extends from the uterine corpus and cervix to an external opening anterior to the anus on the ventral body surface. The vagina is loosely attached to the rectum dorsally and to the urethra ventrally. On the anterior wall of the vaginal opening is a small ventrally extending elevation, the clitoris, covered by skin and hair on its anterior and lateral surfaces. The urethra opens near the tip of the clitoris, within a shallow depression, the clitoral fossa. Small pear-shaped clitoral glands, homologous with the preputial glands of the male, are embedded anterolaterally in the subcutaneous connective tissue; a single duct from each extends to an opening in the lateral wall of the clitoral fossa.
Microscopic anatomy. The wide dorsoventrally flattened lumen of the vagina is lined with stratified squamous epithelium, which undergoes marked changes in number of layers during the estrous cycle ( Chapter 11). The mucosa is folded into longitudinal elevations and contains no glands. The lamina propria is fibrous and the muscularis thin, the inner circular and outer longitudinal layers being intermingled with considerable connective tissue. The outer covering is adventitia continuous with the connective tissues surrounding rectum and urethra. At the vaginal opening, the epithelium is stratified squamous cornified, and the muscularis contains some striated muscle fibers.
The posterior face of the clitoral elevation is covered with vaginal epithelium and the tip, sides, and anterior face are covered by skin with hair. The paired clitoral glands, one on either side at the base of the elevation, are sebaceous type consisting of groups of large, pale-staining, often-vacuolated cells, surrounded by a thin connective tissue capsule. A single large hair follicle occupies the center of each gland. The excretory ducts are lined with stratified squamous epithelium continuous with that of the clitoral fossa.
Within the clitoris, the lining of the urethra is transitional epithelium except at the orifice where it is stratified squamous. A small group of glands, different in structure from the urethral glands of more anterior regions, is located in the lamina propria anterior to the lumen. The aveloli are very small and composed of four or five pyramidal cells with large central nuclei and acidophilic cytoplasm. Their short ducts, which open directly into the urethral lumen, are lined by stratified columnar epithelium. Erectile tissue, comparable to that of the penis but with a finer fibrous network, surrounds the urethra near the tip of the clitoris, and the connective tissue on the anterior face of the clitoris encloses a small bone, homologous with the os penis ( Figure 13-62). There are no muscle layers surrounding the urethra within the clitoris. The connective tissue of the cavernous spaces merges with the surrounding subcutaneous tissue and dermis.
The descriptions of gross and microscopic anatomy in this chapter are based on our observations as well as on those recorded in the literature. In many instances where information on development of organs or regions of the body was unavailable, we included brief summaries or references to embryological and developmental studies. We also included some observations on strain, sex, and age differences in morphology. Under skeleton, bones were listed in regional groups, but no structural details were given. Under the circulatory system heading, only the heart, large arteries and veins, and their principal branches and tributaries were described and no attempt was made to trace or name the smaller arteries, veins, and capillary networks. Descriptions of nervous and muscular systems and of blood and blood-forming tissues were omitted entirely.
Agduhr, E. 1927. Studies on the structure and development of the bursa ovarica and the tuba uterina in the mouse. Acta Zool. 1: 1-133.
Albert, S., and R.M. Johnson. 1960.
Lymph node morphology and metabolism in mammary tumor-susceptible and -resistant mice.
Cancer Res. 20: 246-250.
See also PubMed.
Andrew, W., and N.V. Andrew. 1942. Senile involution of the thyroid gland. Amer. J. Pathol. 18: 849-863.
Andrew, W., and N.V. Andrew. 1957.
An age involution in the small intestine of the mouse; with a description of the fundamental process of lymphoepithelial metamorphosis in intestinal mucosa.
J. Gerentol. 12: 136-149.
See also PubMed.
Arnesen, K. 1958.
The secretory apparatus in the thymus of mice.
Acta Pathol. Microbiol. Scand. 43: 339-349.
See also PubMed.
Auerbach, R. 1960.
Morphogenetic interactions in the development of the mouse thymus gland.
Develop. Biol. 2: 271-284.
See also PubMed.
Auerbach, R. 1964. Experimental analysis of mouse thymus and spleen morphogenesis, p. 95-111. In R.A. Good and A.E. Gabrielsen [ed.] The Thymus in Immunology. Harper & Row, New York.
Baer, P.N., and J.E. Lieberman. 1959.
Observation of some genetic characteristics of the periodontium in three strains of inbred mice.
Oral Surg. 12: 820-829.
See also PubMed.
Bascom, K.F., and H.L. Osterud. 1925. Quantitative studies of the testical. II. Pattern and total tubule length in the testicles of certain common mammals. Anat. Rec. 31: 159-169.
Bateman, N. 1954.
Bone growth: a study of the grey-lethal and microphthalmic mutants of the mouse.
J. Anat. 88: 212-262.
See also MGI.
Billingham, R.E., and W.K. Silvers. 1960.
The melanocytes of mammals.
Quart. Rev. Biol. 35: 1-40.
See also MGI.
Blumenthal, H.T. 1955.
Aging processes in the endocrine glands of various strains of normal mice.
J. Gerentol. 12: 253-267.
See also PubMed.
Borghese, E. 1952.
Foyer d'hématöièse dans la glande surrénale foetale de Mus musculus.
Acta Anat. 16: 54-71.
See also PubMed.
Borodach, G.N., and W. Montagna. 1956.
Fat in skin of the mouse during cycles of hair growth.
J. Invest. Dermatol. 26: 229-232.
See also PubMed.
Braden, A.W.H. 1958. Strain differences in the morphology of the gametes of the mouse. Austral. J. Biol. Sci. 12: 65-71.
Brookreson, A.D., and C.W. Turner. 1959.
Normal growth of mammary gland in pregnant and lactating mice.
Proc. Soc. Exp. Biol. Med. 102: 744-745.
See also PubMed.
Browder, S. 1942.
Factors influencing lung lobation in the mouse. I. Genetic factors: a preliminary report.
Anat. Rec. 83: 31-39.
See also MGI.
Brown, A.L. 1931. An analysis of he developing metanephros in mouse embryos with abnormal kidneys. Amer. J. Anat. 47: 117-172.
Bunker, L.E., Jr. 1959.
Hepatic fusion, a new gene in linkage group I of the mouse.
J. Hered. 50: 40-44.
See also MGI.
Carter, T.C. 1951.
The genetics of luxate mice. I. Morphological abnormalities of heterozygotes and homozygotes.
J. Genet. 50: 277-299.
See also MGI.
Carter, T.C. 1954.
The genetics of luxate mice. IV. Embryology.
J. Geent. 52: 1-35.
See also MGI.
Chase, H.B. 1954.
Growth of the hair.
Physiol. Rev. 34: 113-126.
See also PubMed.
Chase, H.B., and G.J. Eaton. 1959.
The growth of hair follicles in waves.
Ann. N.Y. Acad. Sci. 83: 365-368.
See also PubMed.
Chase, H.B., H. Rauch, and V.W. Smith. 1951.
Critical stages of hair development and pigmentation in the mouse.
Physiol. Zool. 24: 1-8.
See also PubMed.
Chen, J.M. 1952.
Studies on the morphogenesis of the mouse sternum. I. Normal embryonic development.
J. Anat. 86: 373-386.
See also PubMed.
Chiquoine, A.D. 1958.
The identification and electron microscopy of myoepithelial cells in the Harderian gland.
Anat. Rec. 132: 569-584.
See also PubMed.
Clark, S.L., Jr. 1963.
The thymus in mice of strain 129/J, studied with the electron microscope.
Amer. J. Anat. 112: 1-34.
See also PubMed.
Cohn, S.A. 1955.
Histochemical observations on the Harderian gland of the albino mouse.
J. Histochem. Cytochem. 3: 342-353.
See also PubMed.
Cohn, S.A. 1957.
Development of the molar teeth in the albino mouse.
Amer. J. Anat. 101: 295-319.
See also PubMed.
Cook, M.J. 1965. The Anatomy of the Laboratory Mouse. Academic Press, London. 143p.
See the electronic version of The Anatomy of the Laboratory Mouse at MGI.
Coupland, R.E. 1960.
The post-natal distribution of the abdominal chromaffin tissue in the guinea-pig, mouse and white rat.
J. Anat. 94: 244-256.
See also PubMed.
Cowie, A.T., and S.J. Folley. 1961. The mammary gland and lactation, p. 590-642. In W.C. Young [ed.] Sex and Internal Secretions, 3rd ed. Vol I. Wilkins and Wilkins, Baltimore.
Crabtree, C. 1941. The structure of Bowman's capsule as an index of age and sex variations in normal mice. Anat. Rec. 79: 395-413.
Crelin, E.S. 1960. The development of bony pelvic sexual dimorphism in mice. Ann. N.Y. Acad. Sci. 84: 479-512.
Danforth, C.H., and E. Center. 1953.
Development and genetics of a sex-influenced trait in the livers of mice.
Proc. Natl. Acad. Sci. 39: 811-817.
See also PubMed.
Davidson, P., and M.H. Hardy. 1952.
The development of mouse vibrissae in vivo and in vitro.
J. Anat. 86: 342-356.
See also PubMed.
Deane, H.W., and D.W. Fawcett. 1952.
Pigmented interstitial cells showing "brown degeneration" in the ovaries of old mice.
Anat. Rec. 113: 239-245.
See also PubMed.
Delost, P., and P. Chirvan-Nia. 1958.
Différences raciales dans l'involution de la zone X surrénalienne chez la souris adulte vierge.
Compt. Rend. Soc. Biol. 152: 453-455.
See also MGI.
Dry, F.W. 1926. The coat of the mouse (Mus musculus). J. Genet. 16: 287-340.
Dun, R.B., 1958. Growth of the mouse coat. VI. Distribution and number of vibrissae in the house mouse. Austral. J. Biol. Sci. 11: 95-105.
Dunn, T.B. 1944.
Ciliated cells of the thymus of the mouse.
J. Nat. Cancer Inst. 4: 555-557.
See also MGI.
Dunn, T.B. 1949a.
Some observations on the normal and pathological anatomy of the kidney of the mouse.
J. Nat. Cancer Inst. 9: 285-301.
See also MGI.
Dunn, T.B. 1949b.
Melanoblasts in the stroma of the parathyroid glands of strain C58 mice.
J. Nat. Cancer Inst. 10: 725-733.
See also PubMed.
Dunn, T.B. 1954.
Normal and pathologic anatomy of the reticular tissue in laboratory mice, with a classification and discussion of neoplasms.
J. Nat. Cancer Inst. 14: 1281-1434.
See also MGI.
Dunn, T.B., and A. Kessel. 1945. Paneth cells in carcinomas of the small intestine in a mouse and in a rat. J. Nat. Cancer Inst. 6: 113-118.
Engeset, A., and E. Tjötta. 1960. Lymphatic pathways from the tail in rats and mice. Cancer Res. 20: 613-614.
Fawcett, D.W. 1952. A comparison of the histological organization and cytochemical reactions of brown and white adipose tissue. J. Morphol. 90: 363-406.
Fekete, E. 1941. Histology, p. 89-167. In G.D. Snell [ed.] Biology of the Laboratory Mouse. Blakiston, Philadelphia.
Fekete, E. 1946.
A comparative study of the ovaries of mice of the DBA and C57Black strains.
Cancer Res. 6: 263-269.
See also MGI.
Fekete, E. 1950.
Polyovular follicles in the C58 strain of mice.
Anat. Rec. 108: 699-707.
See also MGI.
Fekete, E. 1953.
A morphological study of the ovaries of virgin mice of eight inbred strains showing quantitative differences in their hormone producing componenets.
Anat. Rec. 117: 93-114.
See also MGI.
Ferguson, D.J. 1956.
Endocrine control of mammary glands in C3H mice.
Surgery 39: 30-36.
See also PubMed.
Figge, F.H.J., and R.H. Davidheiser. 1957.
Porphyrin synthesis by mouse Harderian gland extracts: sex, age, and strain variations.
Proc. Soc. Exp. Biol. Med. 96: 437-439.
See also PubMed.
Forsthoefel, P.F. 1959.
The embryological development of the skeletal effects of the luxoid gene in the mouse, including its interactions with the luxate gene.
J. Morphol. 104: 89-142.
See also MGI.
Forsthoefel, P.F. 1963.
Observation on the sequence of blastemal condensations in the limbs of the mouse embryo.
Anat. Rec. 147: 129-137.
See also PubMed.
Fortuyn, A.B.D. 1933. On the age at which the megakaryocytes disappear in the liver of the mouse. Peking Nat. Hist. Bull. 7: 227.
Foster, C.L. 1943. Studies on the parathyroid of the mouse. I. The cytology of the normal gland in relation to its secretory activity. J. Endocrinol. 3: 244-253.
Froud, M.D. 1959. Studies on the arterial system of three inbred strains of mice. J. Morphol. 104: 441-478.
Gaunt, W.A. 1956.
The development of enamel and dentine on the molars of the mouse, with an account of the enamel-free areas.
Acta Anat. 28: 111-134.
See also PubMed.
Gaunt, W.A. 1961.
The presence of apical pits on the lower cheek teeth of the mouse.
Acta Anat. 44: 146-158.
See also PubMed.
Gibbs, H.F. 1941. A study of the post-natal development of the skin and hair of the mouse. Anat. Rec. 80: 61-81.
Gorbman, A. 1947. Functional and morphological properties in the thyroid gland, ultimobranchial body, and persisting ductus pharyngiobranchialis IV of an adult mouse. Anat. Rec. 98: 93-101.
Gorbman, A., and H.A. Bern. 1962. A Textbook of Comparative Endocrinology. Wiley, New York, 468 p.
Green, E.L. 1962.
Quantitative genetics of skeletal variations in the mouse. II. Crosses between four inbred strains.
Genetics 47: 1085-1096.
See also MGI.
Green, E.L., and C.W. McNutt. 1941. Bifurcated xiphisternum and its relationship with short ears in the house mouse. J. Hered. 32: 94-96.
Greene, E.C. 1955. The Anatomy of the Rat. Hafner, New York. 370 p.
Grewal, M.S. 1962.
The development of an inherited tooth defect in the mouse.
J. Embryol. Exp. Morphol. 10: 202-211.
See also MGI.
Grüneberg, H. 1952.
The Genetics of the Mouse, 2nd ed.
Nijhoff, The Hague. 650 p.
See also MGI.
Grüneberg, H. 1963. The Pathology of Development. Wiley, New York. 309 p.
Halmi, N.S., and W.D. Gude. 1954.
The morphogenesis of pituitary tumors induced by radiothyroidectomy in the mouse and the effects of their transplantation on the pituitary body of the host.
Amer. J. Pathol. 30: 403-420.
See also PubMed.
Hardy, M.H. 1949.
The development of mouse hair in vitro with some observations on pigmentation.
J. Anat. 83: 364-384.
See also PubMed.
Hummel, K.P. 1954. Aplasia of the kidney in mice of strain C58. Anat. Rec. 118: 391. (Abstr.)
Hummel, K.P. 1958.
Accessory adrenal cortical nodules in the mouse.
Anat. Rec. 132: 281-295.
See also MGI.
Hunt, R.D. 1963.
Aberrant thyroid tissue in the mouse.
Science 141: 1054-1055.
See also PubMed.
Jacobs, B.B. 1958.
Variation is thyroid morphology of mice.
Proc. Soc. Exp. Biol. Med. 97: 115-118.
See also MGI.
Job, T.T. 1915. The adult anatomy of the lymphatic system in the common rat (Epimys norvegicus). Anat. Rec. 9: 447-458.
Jones, E.C., and P.L. Krohn. 1961.
The relationships between age, numbers of oocytes and fertility in virgin and multiparous mice.
J. Endocrinol. 21: 469-495.
See also PubMed.
Jones, I.C. 1950.
The effect of hypophysectomy on the adrenal cortex of the immature mouse.
Amer. J. Anat. 86: 371-403.
See also PubMed.
Karrer, H.E. 1956.
The ultrastructure of mouse lung; general architecture of capillary and alveolar walls.
J. Biophys. Biochem. Cytol. 2: 241-252.
See also PubMed.
Karrer, H.E. 1958.
The ultrastructure of mouse lung: the alveolar macrophage.
J. Biophys. Biochem. Cytol. 4: 693-700.
See also MGI.
Kelemen, G. 1953.
Nonexperimental nasal and paranasal pathology in hereditarily obese mice.
Arch. Otolaryngol. 57: 143-151.
See also PubMed.
Kelemen, G., and F. Sargent. 1946. Nonexperimental pathologic nasal findings in laboratory rats. Arch. Otolaryngol. 44: 24-42.
Kelsall, M.A. 1946. Number of Peter's patches in mice belonging to high and low mammary tumor strains. Proc. Soc. Exp. Biol. Med. 61: 423-424.
Kent, H.A., Jr. 1960.
Polyovular follicles and multinucleate ova in the ovaries of young mice.
Anat. Rec. 137: 521-524.
See also PubMed.
Kerr, T. 1946. The development of the pituitary of the laboratory mouse. Quart J. Microscop. Sci. 87: 3-29.
Kutuzov, H., and H. Sicher. 1953.
Comparative anatomy of the mucosa of the tongue and the palate of laboratory mouse.
Anat. Rec. 116: 409-425.
See also PubMed.
Lee, Y.B., H. Elias, and I. Davidsohn. 1960. Vascular pattern in the liver of the mouse. Proc. Anim. Care Panel 10: 25-32.
Leppi, T.J. 1964.
A study of the uterine cervix of the mouse.
Anat. Rec. 150: 51-66.
See also PubMed.
Liebelt, R. A. 1959.
Postnatal development of two types of fat depots in the NH and CBA inbred strains of mice.
Amer. J. Anat. 105: 197-218.
See also PubMed.
Little, C.C., and H. MacDonald. 1945.
Abnormalities of the mammae in the house mouse.
J. Hered. 36: 285-288.
See also MGI.
Low, F.N. 1953.
The pulmonary alveolar epithelium of laboratory mammals and man.
Anat. Rec. 117: 241-264.
See also PubMed.
Mann, S.J. 1962. Prenatal formation of hair follicle types. Anat. Rec. 144: 135-142.
Markert, C.L., and W.K. Silvers. 1956.
The effects of genotype and cell environment on melanoblast differentiation in the house mouse.
Genetics 41: 429-450.
See also MGI.
McPhail, M.K., and H.C. Read. 1942. The mouse adrenal. I. Development, degeneration and regeneration of the X-zone. Anat. Rec. 84: 51-73.
Melaragno, H.P., and W. Montagna. 1953.
The tactile hair follicles in the mouse.
Anat. Rec. 115: 129-150.
See also PubMed.
Miller, R.A. 1950.
Cytological phenomena associated with experimental alterations of secretory activity in the adrenal cortex of mice.
Amer. J. Anat. 86: 405-438.
See also PubMed.
Montagna, W., and H.B. Chase. 1950.
Redifferentiation of sebaceous glands in the mouse after total extirpation with methylcholanthrene.
Anat. Rec. 107: 83-91.
See also PubMed.
Munger, B.L. 1958.
A light and electron microscopic study of cellular differentiation in the pancreatic islets of the mouse.
Amer. J. Anat. 103: 275-312.
See also PubMed.
Nandi, S. 1958.
Endocrine control of mammary-gland development and function in the C3H/HeCrgl mouse.
J. Nat. Cancer Inst. 21: 1039-1063.
See also PubMed.
Rauch, H. 1952. Strain differences in liver patterns in mice. Genetics 37: 617. (Abstr.)
Raynaud, A. 1961. Recent studies on the morphogenesis of the mammary gland of the mouse. p. 30-42. In S.K. Kon and A.T. Cowie [ed.] Milk: The Mammary Gland and its Secretion. Vol I. Academic Press, London.
Richardson, F.L. 1951.
Further studies on the mammary gland development in male mice at nine weeks of age.
Anat. Rec. 111: 669-694.
See also MGI.
Richardson, F.L. 1953.
The mammary gland development in normal and castrate male mice at nine weeks of age.
Anat. Rec. 117: 449-465.
See also MGI.
Richardson, F.L., and G. Hall. 1960.
Mammary tumors and mammary-gland development in hybrid mice treated with diethylstilbestrol for varying periods.
J. Nat. Cancer Inst. 25: 1023-1039.
See also PubMed.
Richardson, F.L., and K.P. Hummel. 1959.
Mammary tumors and mammary-gland development in virgin mice of strains C3H, RIII, and their F1 hybrids.
J. Nat. Cancer Inst. 23: 91-107.
See also PubMed.
Richardson, F.L., and B. Pearson. 1954.
Alkaline phosphatase activity during carcinogenesis of mammary tumors in mice implanted with stilbestrol pellets.
J. Nat. Cancer Inst. 14: 1123-1135.
See also PubMed.
Russell, E.S. 1946.
A quantitative histological study of the pigment found in the coat-color mutants of the house mouse. I. Variable attributes of the pigment granules.
Genetics 31: 327-346.
See also PubMed.
Rytand, D.A. 1938. The number and size of mammalian glomeruli as related to kidney and body weight, with methods for their enumeration and measurement. Amer. J. Anat. 62: 507-520.
Santisteban, G.A. 1960.
The growth and involution of lymphatic tissue and its interrelationships to aging and growth of the adrenal glands and sex organs in CBA mice.
Anat. Rec. 136: 117-126.
See also PubMed.
Sharma, K.N. 1960.
Genetics of gametes. IV. The phenotype of mouse spermatozoa in four inbred strains and their F1 crosses.
Proc. Roy. Soc. Edinb. B 68: 54-71.
See also MGI.
Sidman, R.L., and D.W. Fawcett. 1954.
The effect of peripheral nerve section on some metabolic responses of brown adipose tissue in mice.
Anat. Rec. 118: 487-507.
See also PubMed.
Smith, C. 1964. The microscopic anatomy of the thymus, P. 71-84. In R.A. Good and A.E. Gabrielsen [ed.] The Thymus in Immunology. Harper and Row, New York.
Smith, C., and C.P. Clifford. 1962.
Histochemical study of aberrant parathyroid glands associated with the thymus of the mouse.
Anat. Rec. 143: 229-238.
See also PubMed.
Smith, C., and B.K. Hénon. 1959.
Histological and histochemical study of high endothelium of post-capilary veins of the lymph node.
Anat. Rec. 135: 207-214.
See also PubMed.
Smith, C., and L.N. Ireland. 1941. Studies on the thymus of the mammal. I. The distribution of argyrophil fibers from birth through old age in the thymus of the mouse. Anat. Rec. 79: 133-154.
Smith, C., E.C. Thatcher, D.Z. Kraemer, and E.S. Holt. 1952. Studies on the thymus of the mammal. VI. The vascular pattern of the thymus of the mouse and its changes during aging. J. Morphol. 91: 199-220.
Snook, T. 1950.
A comparative study of the vascular arrangements in mammalian spleens.
Amer. J. Anat. 87: 31-78.
See also PubMed.
Stein, K.F. 1957.
Genetical studies on the skeleton of the mouse. XXI. The girdles and the long limb bones.
J. Genet. 55: 313-324.
See also MGI.
Straile, W.E. 1960. Sensory hair follicles in mammalian skin: the tylotrich follicle. Amer. J. Anat. 106: 133-148.
Suntzeff, V., and P. Angeletti. 1961. Histological and histochemical changes in intestines of mice with aging. J. Gerentol. 16: 225-229.
Van Ebbenhorst Tengbergen, W.J.P.R. 1955.
The morphology of the mouse anterior pituitary during the oestrous cycle.
Acta Endocrinol. 18: 213-218.
See also PubMed.
Van Heyningen, H.E. 1961.
The initiation of thyroid function in the mouse.
Endocrinology 69: 720-727.
See also MGI.
Von Bartheld, F., and J. Moll. 1954.
The vascular system of the mouse epiphysis with remarks on the comparative anatomy of venous trunks in the epiphyseal area.
Acta Anat. 22: 227-235.
See also PubMed.
Walker, B.E., and F.C. Fraser. 1956. Closure of the secondary palate in three strains of mice. J. Embryol. Exp. Morphol. 4: 176-189.
Webster, S.H., and E.J. Liljegren. 1955.
Organ body-weight ratios for certain organs of laboratory animals. III. White Swiss mouse.
Amer. J. Anat. 97: 129-153.
See also PubMed.
Wellings, S.R., K.B. DeOme, and D.R. Pitelka. 1960.
Electron microscopy of milk secretion in the mammary gland of the C3h/Crgl mouse. I. Cytomorphology of the prelactating and the lactating gland.
J. Nat. Cancer Inst. 25: 393-421.
See also PubMed.
Wimsatt, W.A., and C.M. Waldo. 1945.
The normal occurrence of a perioneal opening in the bursa ovarii of the mouse.
Anat. Rec. 93: 47-53.
See also MGI.
Wirtschafter, Z.T., and J.K. Tsujimura. 1961.
The sesamoid bones in the C3H mouse.
Anat. Rec. 139: 399-408.
See also MGI.