Analysis Tools
mortality/aging
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• about half die within a few hours of birth because of bleeding in several organs
(J:56003)
• neonates die shortly after birth because of cardio-respiratory distress
(J:75507)
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• those surviving the neonatal period die before P14 (exhibit 51% survival at P1, 27% at P4-P6, 6% at P9 and 0.5% at P12)
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growth/size/body
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• 43% lack incisors
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cleft palate
(
J:81698
)
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• seen in 74% of mutants
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• neonates surviving the perinatal period have normal body weights at birth but fail to gain weight
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cardiovascular system
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• about 50% of neonates exhibit severe DiGeorge syndrome-like vessel malformations
(J:81698)
• vascular densities in the interventricular septum are lower in neonates that die in the perinatal period and the vessels are grossly abnormal and dilated
(J:81698)
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• fewer and smaller arterioles in the retina
• less than half of the number of arterioles grow out over only 35% of the retina and 53% of the vascular bed
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• fewer renal arteries
(J:75507)
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• persistence of the cartoid duct segment between the left carotid and subclavian artery
• the type-B interruption is associated with persistence of the ductus caroticus, resulting in a cervical aortic arch
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• about 10% of embryos exhibit a dominant right dorsal aorta
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• E14.5 embryos and neonates have remodeling defects of the 4th, 6th and, less frequently, 3rd pharyngeal arch arteries
• while the 3rd, 4th and 6th pharyngeal arch arteries are present by E10-10.5, subsequent malformations include hypoplasia, an irregular lumen size, and signs of regression in vessels that should normally persist
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• malformations of the 4th arch artery include a persistence of the carotid duct segment between the left carotid and subclavian artery and a descending aorta
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• abnormal development of the 6th arch artery; hypoplasia of the pulmonary trunk or malformations of the ductus arteriosus leading to an absent or right-sided ductus
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• observe aortico-pulmonary collateral arteries
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• hypoplasia of the pulmonary trunk in E13.5-14.5 embryos
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• malformations of the 4th arch artery include a right 4th arch interruption together with an aberrant subclavian artery, resulting in a retroesophageal right subclavian artery
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• the type-B interruption is associated with persistence of the ductus caroticus, resulting in a cervical aortic arch
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• malformations of the 4th arch artery include type-B left 4th aortic arch interruption
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• malformations of the 4th arch artery include a right-sided aortic arch
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• malformations of the 4th arch artery include a double aortic arch
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• malformations of the 3rd arch artery result in a double left or right carotid artery
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• defective capillary vessel formation results in larger inter-capillary distances in hearts and an increase in myocyte-to-capillary ratios at P12
(J:56003)
• capillaries in hearts are irregular, tortuous and slightly dilated, indicative of incomplete vessel remodeling
(J:56003)
• exhibit more numerous, dilated and fragile capillaries in the central retina
(J:75507)
• capillary density and size in the septum are less affected in those mice that die 2 weeks after birth (rather than perinatally)
(J:81698)
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• do not observe a change in capillary density from birth to P12 as in wild-type, indicating a 400% reduction in density
• capillary densities in skeletal muscles are also decreased
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• slightly dilated in the heart
(J:56003)
• in the retina
(J:75507)
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• capillaries in hearts are irregular, tortuous and slightly dilated, indicative of incomplete vessel remodeling
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• outgrowth of capillaries and pericyte coverage is impaired in the retinal vasculature, which remains more immaturely remodeled
(J:56003)
• only a primitive vascular labyrinth of capillary-like vessels with uniform size develop by P5
(J:75507)
• periendothelial cell (PEC) recruitment is delayed, with only scattered PECs detected in and around the optic disc
(J:75507)
• the capillary bed covers the retina only over 2/3 in the small fraction of mice that survive to P9
(J:75507)
• exhibit more numerous and dilated capillaries in the central retina
(J:75507)
• fewer periendothelial cells surround the arterioles, venules, and capillaries
(J:75507)
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• capillary growth in renal glomeruli is retarded
(J:56003)
• fewer renal arteries
(J:75507)
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• fewer SMA-stained kidney arteries are detected at all postnatal ages relative to wild-type controls
• although lobar arteries develop normally, further branching into arcuate, interlobular, and afferent/efferent arterioles progressively
• at P0.5 and P3, the number of renin-expressing branch points per kidney section is reduced relative to that in wild-type kidneys
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• by P6, the number of afferent arterioles is reduced to ~50% of that in wild-type kidneys
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• by P6, the number of interlobular arteries is reduced to one-third of that in wild-type kidneys
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• by P6, the number of efferent arterioles is reduced to ~50% of that in wild-type kidneys
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• at P0.5, mutant glomeruli exhibit fewer and disordered capillary loops, unlike wild-type glomeruli
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• at E15.5 to P6, fewer glomeruli are vascularized, as revealed by CD34-staining
• by P6, ~40% fewer glomeruli contain CD34-positive endothelial cells; however, endothelial fenestration occurs as in wild-type controls
• endothelial cells appear to detach from their underlying basement membrane and show signs of cellular degeneration and death (blebbing, vacuolization, nuclear disintegration)
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• at E15.5 to P6, the number of laminin-positive capillary loops per glomerulus is reduced relative to that in wild-type controls
• when capillary loops form, they fail to expand into a complex tuft and eventually disintegrate
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• by P6, peritubular capillaries remain dilated, appear tortuous and irregular, and lack symmetric patterning
• endothelial cells in peritubular capillaries contain luminal cytoplasmic protrusions and blebs or appear thin and elongated, unlike wild-type peritubular capillaries which contain intact, regular, and tightly interacting endothelial cells
• at P6, the distance between neighboring peritubular capillaries is enlarged, suggesting kidney ischemia
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• fewer pericytes are detected around peritubular capillaries relative to wild-type kidneys
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• exhibit signs of regression in vessels of the pharyngeal arch that should normally persist
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• defects most profound in the subendomyocardium
• capillary and coronary angiogenesis is impaired in the right ventricle and in the atria
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• fewer and smaller venules in the retina
• only half of the number of venules are seen in the retina at P9, but have a normal lumen size, and they grow out over only 52% of the retinal radius, but over 80% of the vascular bed
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• mutants that die in the perinatal period exhibit a wide spectrum of cardiac defects, including Tetralogy of Fallot, however do not observe cardiac defects in those that survive postnatally
(J:81698)
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• at P6, cardiomyocytes progressively lose perinuclear myofibrils, exhibit a reduction in the number of gap junctions between cardiomyocytes, either reduced or disorganized desmin, distorted nuclei with increased amounts of glycogen, irregular mini-mitochondria, and increased levels of fetal genes that are re-introduced during the course of ischemic heart disease
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• cardiomyoctes are slightly larger at P12
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• detect atrophy and degeneration of cardiomyocytes beyond P6; cardiomyocytes show loss of myofibrils, costamere disruption, lipid-like inclusions, irregular nuclear shape, and a nonspecified cytoplasm filled with necrotic remnants and cellular debris
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• vascular densities in the interventricular septum are lower in neonates that die in the perinatal period and the vessels are grossly abnormal and dilated
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• hearts contain fewer coronary vessels, which show less smooth muscle alpha-actin staining
(J:56003)
• fewer coronary arteries
(J:75507)
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• ventricular septal defect
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• myocardial ischemia; regional blood flow through the myocardium at P6 is 0.7 ml/min per g compared to 2.9 in wild-type
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hemorrhage
(
J:56003
)
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• about half die within a few hours of birth because of bleeding in several organs
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• fragile capillaries in the retina cause hemorrhages
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• exhibit dysmorphic, weak heart contractions
• depressed left ventricular contractility; enlarged systolic left ventricular and diastolic left ventricular diameters, impaired fractional shortening, and reduced aortic outflow velocity
• suffer severe left ventricular pump failure and show signs of right ventricular failure, including accumulation of ascitic fluid and increased liver-to-body weight
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• depressed left ventricular relaxation
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• left ventricular pressure is further reduced during periods of spontaneous arrhythmia
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• slower heart rates in conscious P6 mice
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• electrical pulse shows signs of dispersion and heterogeneity
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• prolonged QRS interval at P6
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• exhibit ST-segment depressions in mice at rest
• rapidly develop considerable ST-segment elevations when ventilation is stopped
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• exhibit T-wave inversions in mice at rest
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behavior/neurological
muscle
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• at P6, cardiomyocytes progressively lose perinuclear myofibrils, exhibit a reduction in the number of gap junctions between cardiomyocytes, either reduced or disorganized desmin, distorted nuclei with increased amounts of glycogen, irregular mini-mitochondria, and increased levels of fetal genes that are re-introduced during the course of ischemic heart disease
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• cardiomyoctes are slightly larger at P12
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• detect atrophy and degeneration of cardiomyocytes beyond P6; cardiomyocytes show loss of myofibrils, costamere disruption, lipid-like inclusions, irregular nuclear shape, and a nonspecified cytoplasm filled with necrotic remnants and cellular debris
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• exhibit dysmorphic, weak heart contractions
• depressed left ventricular contractility; enlarged systolic left ventricular and diastolic left ventricular diameters, impaired fractional shortening, and reduced aortic outflow velocity
• suffer severe left ventricular pump failure and show signs of right ventricular failure, including accumulation of ascitic fluid and increased liver-to-body weight
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• depressed left ventricular relaxation
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• sarcomere rarefication
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renal/urinary system
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• capillary growth in renal glomeruli is retarded
(J:56003)
• fewer renal arteries
(J:75507)
|
|
• fewer SMA-stained kidney arteries are detected at all postnatal ages relative to wild-type controls
• although lobar arteries develop normally, further branching into arcuate, interlobular, and afferent/efferent arterioles progressively
• at P0.5 and P3, the number of renin-expressing branch points per kidney section is reduced relative to that in wild-type kidneys
|
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• by P6, the number of afferent arterioles is reduced to ~50% of that in wild-type kidneys
|
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• by P6, the number of interlobular arteries is reduced to one-third of that in wild-type kidneys
|
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• by P6, the number of efferent arterioles is reduced to ~50% of that in wild-type kidneys
|
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• at P0.5, mutant glomeruli exhibit fewer and disordered capillary loops, unlike wild-type glomeruli
|
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• at E15.5 to P6, fewer glomeruli are vascularized, as revealed by CD34-staining
• by P6, ~40% fewer glomeruli contain CD34-positive endothelial cells; however, endothelial fenestration occurs as in wild-type controls
• endothelial cells appear to detach from their underlying basement membrane and show signs of cellular degeneration and death (blebbing, vacuolization, nuclear disintegration)
|
|
• at E15.5 to P6, the number of laminin-positive capillary loops per glomerulus is reduced relative to that in wild-type controls
• when capillary loops form, they fail to expand into a complex tuft and eventually disintegrate
|
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• by P6, peritubular capillaries remain dilated, appear tortuous and irregular, and lack symmetric patterning
• endothelial cells in peritubular capillaries contain luminal cytoplasmic protrusions and blebs or appear thin and elongated, unlike wild-type peritubular capillaries which contain intact, regular, and tightly interacting endothelial cells
• at P6, the distance between neighboring peritubular capillaries is enlarged, suggesting kidney ischemia
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• mesangial cells gradually disappear as glomeruli become sclerotic and loose their capillary network
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• at P0.5, the GBM often displays a variable shape and thickness, and appears more irregular and tortuous
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• the GBM often displays a variable thickness in mature glomeruli after E17.5
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• most sclerotic glomeruli accumulate an unusual amount of collagen type IV, fibrin, fibronectin, and laminin
• excessive matrix deposition is already detectable in fetal mature glomeruli after E17.5
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• at P0.5, P3 and P6, the number of sclerotic/total glomeruli is 0/52 (0%), 7/107 (6.5%), and 18/104 (17%), respectively, unlike in wild-type kidneys where no sclerotic glomeruli are observed
• at P6, abnormal accumulation of laminin is noted in mutant sclerotic glomeruli but not in mature wild-type glomeruli
• in sclerotic glomeruli, the entire capillary bed often disappears and is replaced by amorphous granular necrotic debris
• however, parietal epithelial cells in the capsule of Bowman and podocytes remain normal in most glomeruli and persist even when glomeruli become sclerotic
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• at P0.5, P3, and P6, homozygotes display ~25% fewer glomeruli/kidney section relative to wild-type controls
• however, glomerular density (i.e., glomeruli per mm2) is not reduced because kidneys are smaller
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• by P6, mutant sclerotic glomeruli are ~3-fold larger than mature wild-type glomeruli
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• at P3, the nephrogenic cortex is reduced by ~25% relative to that in wild-type kidneys
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small kidney
(
J:111504
)
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• however, kidney growth is proportional to that of total body, with no significant differences in kidney/total body weight ratio at P0.5 and P6
• at P0.5, P3, and P6, mutant kidneys are smaller than wild-type
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• at P6, fewer but often enlarged and tortuous loops of Henle are observed, unlike in wild-type kidneys
• ultrastructural signs of ischemia are detected in the loops of Henle, unlike in wild-type kidneys
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• at P0.5, P3, and P6, fewer proximal convoluted tubules are observed relative to wild-type controls
• ultrastructural signs of ischemia are detected in the proximal tubules, unlike in wild-type kidneys
• in contrast, distal convoluted tubules are of normal size, number and morphology
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• at P3 and P6, proximal convoluted tubules appear enlarged relative to those in wild-type kidneys
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pale kidney
(
J:111504
)
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• mutant kidneys are generally paler than wild-type
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• at P6, glomerular filtration is impaired, as shown by elevated levels of plasma creatinine and urea
• GFR cannot be determined by measuring creatinine clearance, as mutant neonates are fragile
• after i.v injection of neutral horseradish peroxidase (HRP), abundant HRP leaks through the glomerular filter into the urine and is detected on the brush border, in microvilli, and in intracellular endocytic vesicles in proximal tubules, unlike in wild-type kidneys
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• ultrastructural signs of ischemia (mitochondrial clarification, disrupted mitochondrial cristae, cytoplasmic vacuolization, intracellular edema, swelling, and plasmalemma blebbing) are detected in the proximal tubules and loops of Henle, unlike in wild-type kidneys
• at P6, the distance between neighboring peritubular capillaries is enlarged, suggesting kidney ischemia
|
vision/eye
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• outgrowth of capillaries and pericyte coverage is impaired in the retinal vasculature, which remains more immaturely remodeled
(J:56003)
• only a primitive vascular labyrinth of capillary-like vessels with uniform size develop by P5
(J:75507)
• periendothelial cell (PEC) recruitment is delayed, with only scattered PECs detected in and around the optic disc
(J:75507)
• the capillary bed covers the retina only over 2/3 in the small fraction of mice that survive to P9
(J:75507)
• exhibit more numerous and dilated capillaries in the central retina
(J:75507)
• fewer periendothelial cells surround the arterioles, venules, and capillaries
(J:75507)
|
|
• fragile capillaries in the retina cause hemorrhages
|
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• no signs of hyaloid regression are seen at P9, and the hyaloid vessels appear dilated and tortuous, however the hyaloid arteries do not penetrate the retina or make connections with the retinal vasculature
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nervous system
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• of gonadotropin-releasing hormone neurons
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• caudally migrating somata of facial branchiomotor neurons prematurely turns dorsally and dives through the basal plate in ectopic anterior locations
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• facial motor nuclei appear elongated or dumbbell-shaped
• in 7 of 9 mutants, one or both facial motor nuclei are shifted anteriorly, however facial nerve is not defasciculated
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• reduced gonadotropin-releasing hormone neurons at E14.5, E15.5 and E18.5
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craniofacial
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• E14.5 embryos and neonates have remodeling defects of the 4th, 6th and, less frequently, 3rd pharyngeal arch arteries
• while the 3rd, 4th and 6th pharyngeal arch arteries are present by E10-10.5, subsequent malformations include hypoplasia, an irregular lumen size, and signs of regression in vessels that should normally persist
|
|
• malformations of the 4th arch artery include a persistence of the carotid duct segment between the left carotid and subclavian artery and a descending aorta
|
|
• abnormal development of the 6th arch artery; hypoplasia of the pulmonary trunk or malformations of the ductus arteriosus leading to an absent or right-sided ductus
|
|
• cranial sutures between the frontal and parietal bones fail to close properly
|
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• 43% lack incisors
|
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• vascular density in the mandible is significantly reduced and the vessels are abnormally dilated and tortuous
|
cleft palate
(
J:81698
)
|
• seen in 74% of mutants
|
embryo
|
• E14.5 embryos and neonates have remodeling defects of the 4th, 6th and, less frequently, 3rd pharyngeal arch arteries
• while the 3rd, 4th and 6th pharyngeal arch arteries are present by E10-10.5, subsequent malformations include hypoplasia, an irregular lumen size, and signs of regression in vessels that should normally persist
|
|
• malformations of the 4th arch artery include a persistence of the carotid duct segment between the left carotid and subclavian artery and a descending aorta
|
|
• abnormal development of the 6th arch artery; hypoplasia of the pulmonary trunk or malformations of the ductus arteriosus leading to an absent or right-sided ductus
|
endocrine/exocrine glands
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• absent in 4 of 12 neonates, and when present, they are associated with an ectopic thymic lobe
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• vessel density and total vascular volume are reduced in the thymus
|
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• 5 of 12 mutants either have a hypoplastic, absent, or ectopically located thymus
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• 5 of 12 mutants either have a hypoplastic, absent, or ectopically located thymus
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• 5 of 12 mutants either have a hypoplastic, absent, or ectopically located thymus
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homeostasis/metabolism
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• at P6, plasma creatinine levels are significantly higher than those in wild-type controls
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• at P6, plasma urea levels are significantly higher than those in wild-type controls
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• homozyogotes that die in the perinatal period become cyanotic immediately after birth
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immune system
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• vessel density and total vascular volume are reduced in the thymus
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• 5 of 12 mutants either have a hypoplastic, absent, or ectopically located thymus
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• 5 of 12 mutants either have a hypoplastic, absent, or ectopically located thymus
|
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• 5 of 12 mutants either have a hypoplastic, absent, or ectopically located thymus
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• fraction of circulating lymphocytes is decreased
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skeleton
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• cranial sutures between the frontal and parietal bones fail to close properly
|
|
• 43% lack incisors
|
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• vascular density in the mandible is significantly reduced and the vessels are abnormally dilated and tortuous
|
hematopoietic system
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• vessel density and total vascular volume are reduced in the thymus
|
|
• 5 of 12 mutants either have a hypoplastic, absent, or ectopically located thymus
|
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• 5 of 12 mutants either have a hypoplastic, absent, or ectopically located thymus
|
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• 5 of 12 mutants either have a hypoplastic, absent, or ectopically located thymus
|
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• fraction of circulating lymphocytes is decreased
|
digestive/alimentary system
cleft palate
(
J:81698
)
|
• seen in 74% of mutants
|
respiratory system
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• observe aortico-pulmonary collateral arteries
|
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• a fraction of newborn homozygotes that die of respiratory distress syndrome exhibit increased alveolar septal thickness and abundant immature PAS+ (glycogen-rich) pneumocytes, indicating lung prematurity
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atelectasis
(
J:77480
)
|
• in a fraction of newborn homozygotes, lung aeration (percentage of total surface filled with air) fails to increase after birth
|
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• a fraction of newborn homozygotes that die of respiratory distress syndrome display a significantly increased alveolar septal thickness at birth
|
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• a fraction of newborn homozygotes die of respiratory distress syndrome
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cellular
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• exhibit signs of regression in vessels of the pharyngeal arch that should normally persist
|
|
• mesangial cells gradually disappear as glomeruli become sclerotic and loose their capillary network
|
|
• of gonadotropin-releasing hormone neurons
|
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• caudally migrating somata of facial branchiomotor neurons prematurely turns dorsally and dives through the basal plate in ectopic anterior locations
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| DiGeorge syndrome | DOID:11198 |
OMIM:188400 |
J:81698 | |
| newborn respiratory distress syndrome | DOID:12716 |
OMIM:267450 |
J:77480 | |
