Analysis Tools
reproductive system
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• total sperm numbers in mutant cauda epididymides are 26%-45% lower than those of controls
• numbers of mutant sperm subclassified as motile, progressive, rapid, medium or slow are also reduced by 27%-35%
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• ~20%-30% of mutant sperm heads and tails are abnormal relative to wild-type
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• some cross section of mutant sperm tails display a double axoneme and associated structures enveloped by a common cytoplasm
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• some mutant sperm heads are associated with a moderately dense amorphous material
• some mutant sperm heads include large masses of cytoplasm, containing large vacuoles, membranous whorls, aggregations of mitochondria, and occasionally cross sectional profiles of tails
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• at times, mutant acrosomes appear to be peeling off the nucleus
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• the nuclei of mutant sperm heads are often distorted or lobulated
• in some cases, more than one nucleus are found in a common cytoplasm
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• at P21, only a few, if any, round spermatids are observed in some mutant seminiferous tubules
• at P35, no elongating spermatids (step 11-13) are observed, unlike in wild-type and heterozygous controls
• homogenization-resistant elongated spermatids (steps 14-16) are first detectable only by P42; however, significantly less homogenization-resistant spermatids are noted at all test intervals, with differences (64%-87%) becoming severe from P63 onward
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• at 12 months of age, male homozygotes show a 20% increase in the percentage of static sperm relative to wild-type males
• mutant sperm velocities (VAP, VSL, and VCL) and the amplitude of the lateral head displacements (ALH) are slightly but significantly lower than wild-type
• however, the beat cross frequency, head elongation ratio of sperm, and various other relative ratios (STR and LIN) remain normal
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• the ratio of 4C:2C (where 4C = primary spermatocytes and G2 spermatogonia and 2C = spermatogonia and testicular somatic cells) is significantly reduced relative to wild-type and heterozygous controls at all age groups tested, suggesting a reduction in the % of cells undergoing spermatogonial proliferation
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• at 3-4 months of age, the mutant ovary displays only a few preantral follicles as well as hyperplasia of interstitial tissue and a lack of corpora lutea
(J:65577)
• the mutant ovarian stroma is hypertrophied and displays hyperplastic cells and features typical of steroid hypersecretion
(J:65577)
• at 3-5 months of age, large islands of polygonal cells with a round central nucleus and abundant cytoplasm-containing lipid droplets are observed; these resemble luteinized cells that are steroidogenically active
(J:70933)
• by 12-15 months of age, tumor containing ovaries have solid or solid and cystic consistency and a yellowish-white color; two females had huge balloon-like right ovaries filled with copious liquid
(J:70933)
• at 12 months of age, nonaffected ovaries contained neither oocytes nor any recognizable follicles; multiple areas of calcification were observed
(J:70933)
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(J:65577)
• at 3-5 months of age
(J:70933)
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• follicular development is blocked before antrum formation, with atresia in a few remaining follicles that have any semblance of antrum
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small ovary
(
J:70933
)
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• the nonaffected ovary in tumor-bearing female mutants is quite small, weighing only ~2.3 mg
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• at 3-4 months of age, mutant ovarian weight is reduced by 58% relative to wild-type
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ovary cyst
(
J:70933
)
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• by 12-15 months of age, 2 of the 23 tumor bearing females developed large ovarian cysts, not observed in mutants at 2-5 months or in wild-type females at any stage
• all ovarian cysts were confined to the right ovaries
• in a few ovaries, cysts were lined by a columnar epithelium with occasional vacuoles, with subjacent stroma containing vacuolated plump cells; epithelial cells ranged from a single cell-lining to a stratified cell population thrown into papillary folds
• one cyst displayed a transition from a simple columnar epithelium to a stratified epithelium with a papillary configuration
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• at P21, male homozygotes show a ~505 reduction in the number of Sertoli cells per cross section of seminiferous tubule relative to wild-type and heterozygous controls
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• at P7-, P14- and P49, the diameter of mutant seminiferous tubules is smaller than that of wild-type and heterozygous controls
• at P28, both the tubular and luminal diameter are severely reduced
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• male homozygotes display a delay in testicular development due to loss of FSH-receptor signaling
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• at P7 and thereafter, male homozygotes display significantly reduced testis weights relative to wild-type and heterozygotes controls
• at 4-6 weeks of age, mutant testes weigh only ~25% of wild-type testes
• overall reduction in testicular size is due to decreases in Sertoli and spermatogonial proliferation
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• by 12-15 months of age, 92% (23 of 25) mutant females developed sex cord-stromal ovarian tumors of the Sertoli-Leydig cell type, not observed in mutants at 2-5 months or in wild-type females at any age
• the remaining two mutants had atrophic ovaries with no macroscopic signs of tumorigenesis or cysts
• 91% of ovarian neoplasia was confined to a single ovary; the remaining 9% involved both ovaries
• 74% of ovarian tumors were unilateral and confined exclusively to the right ovary while 17% were confined to the left ovary
• the mean weight of the right ovary with tumor or cyst was ~36 mg while the mean weight of the left affected ovary was ~24.7 mg
• the affected ovary was enlarged 12-16 times at the age of ~7-10 months
• some ovarian tumors showed an equal admixture of tubular structures (Sertoli cells) and vacuolated plump stromal cells (Leydig cells); others were nearly devoid of tubular elements, consisting almost entirely of clusters of Leydig type cells; a focal microfollicular change in neoplastic cells, reminiscent of granulosa cells, was occasionally observed
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• at the age of 6-7 months, all female homozygotes display clitorimegaly
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• at 3-4 months of age, mutant uteri are thin (thread like), estrogen deprived, and covered with unusual high amount of fat
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• at 3-4 months of age, the glandular elements of the mutant endometrium are less complex relative to wild-type and heterozygous controls, indicating that estrogenic actions are sparse
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• at 3-4 months, myometrial hypoplasia is more pronounced in the outer layer of smooth muscle than in the inner layer
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• at 3-4 months of age, mutant uterine weight is reduced by 70% relative to wild-type
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thin uterus
(
J:65577
)
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• at 3-4 months of age, uterine epithelium, stromal, and myometrial layers are severely reduced
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• at 3-4 months of age, mutant uteri are thread-like and display a reduced diameter due to atrophy of the myometrium, endometrial stroma, and epithelium compartments
• notably, estradiol-17beta administration induces uterine growth in mutant female mice within 48 hrs after estrogen treatment
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• at 3-4 months of age, the mutant vaginal epithelium consists of only 2-3 layers of atrophic cells
• no estrogen-induced cornified epithelial cells are identified in the mutant vaginal smear
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• unlike in wild-type and heterozygous females, vaginal opening fails to occur at proestrus
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• at 3-4 months, mutant vaginal weight is reduced by 40% relative to wild-type
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• at P42, mutant cauda epididymides show absence of sperm whereas the cauda of wild-type and heterozygous males is filled with sperm
• however, by P49, all three genotypes exhibit sperm in the lumen of cauda epididymis, indicating that spermiogenesis and/or epididymal transit is delayed in male homozygotes
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• at 3 and 6 months of age, the outer profile, luminal, and epithelial areas of tubules from mutant caput epididymides are significantly smaller than wild-type
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• at 3 months of age, only the epithelial areas of mutant corpus epididymides are significantly smaller than wild-type
• by 6 months of age, the outer profile, luminal, and epithelial areas from mutant corpus epididymides are all significantly smaller than wild-type
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• male homozygotes show a dramatic size reduction of the epididymal epithelium
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• mutant epididymides are significantly lighter than wild-type from day 28 (P28) onward
• however, no significant reduction in epididymal weight are detected until P21
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• the time taken to produce the first litter by males homozygotes is significantly longer relative to wild-type males
• whereas wild-type males are estimated to produce the minimum number of sperm required to successfully impregnate a female by ~56 days, male homozygotes attain this level by 77 days
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• male homozygotes display a delay in spermatogenesis and fertilizing ability as they mature
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anovulation
(
J:70933
)
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• at 3-5 months of age
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• most mutant vaginal smears do not contain estrogen-induced epithelial cornified cells but are composed of leukocytes and occasional epithelial cells
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• female homozygotes show no evidence of cyclic behavior in >1 yr of observation
(J:65577)
• at 3-5 months of age, mutant females are acyclic
(J:70933)
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• the size of the first litter produced by maturing (6-wk-old) male homozygotes is lower than that of wild-type males (4.6 vs 7, respectively)
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• the number of pups sired by male homozygotes is lower than that produced by wild-type males
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behavior/neurological
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• starting at ~4-5 months of age, all mutants display a hunchback appearance and cannot be laid flat due to the pivoting back unless secured to the dissecting board
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endocrine/exocrine glands
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• at 3-4 months of age, the glandular elements of the mutant endometrium are less complex relative to wild-type and heterozygous controls, indicating that estrogenic actions are sparse
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• at 3-4 months of age, the mutant ovary displays only a few preantral follicles as well as hyperplasia of interstitial tissue and a lack of corpora lutea
(J:65577)
• the mutant ovarian stroma is hypertrophied and displays hyperplastic cells and features typical of steroid hypersecretion
(J:65577)
• at 3-5 months of age, large islands of polygonal cells with a round central nucleus and abundant cytoplasm-containing lipid droplets are observed; these resemble luteinized cells that are steroidogenically active
(J:70933)
• by 12-15 months of age, tumor containing ovaries have solid or solid and cystic consistency and a yellowish-white color; two females had huge balloon-like right ovaries filled with copious liquid
(J:70933)
• at 12 months of age, nonaffected ovaries contained neither oocytes nor any recognizable follicles; multiple areas of calcification were observed
(J:70933)
|
|
|
(J:65577)
• at 3-5 months of age
(J:70933)
|
|
|
• follicular development is blocked before antrum formation, with atresia in a few remaining follicles that have any semblance of antrum
|
small ovary
(
J:70933
)
|
|
• the nonaffected ovary in tumor-bearing female mutants is quite small, weighing only ~2.3 mg
|
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• at 3-4 months of age, mutant ovarian weight is reduced by 58% relative to wild-type
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ovary cyst
(
J:70933
)
|
|
• by 12-15 months of age, 2 of the 23 tumor bearing females developed large ovarian cysts, not observed in mutants at 2-5 months or in wild-type females at any stage
• all ovarian cysts were confined to the right ovaries
• in a few ovaries, cysts were lined by a columnar epithelium with occasional vacuoles, with subjacent stroma containing vacuolated plump cells; epithelial cells ranged from a single cell-lining to a stratified cell population thrown into papillary folds
• one cyst displayed a transition from a simple columnar epithelium to a stratified epithelium with a papillary configuration
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• at P21, male homozygotes show a ~505 reduction in the number of Sertoli cells per cross section of seminiferous tubule relative to wild-type and heterozygous controls
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• at P7-, P14- and P49, the diameter of mutant seminiferous tubules is smaller than that of wild-type and heterozygous controls
• at P28, both the tubular and luminal diameter are severely reduced
|
|
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• male homozygotes display a delay in testicular development due to loss of FSH-receptor signaling
|
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|
• at P7 and thereafter, male homozygotes display significantly reduced testis weights relative to wild-type and heterozygotes controls
• at 4-6 weeks of age, mutant testes weigh only ~25% of wild-type testes
• overall reduction in testicular size is due to decreases in Sertoli and spermatogonial proliferation
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• by 12-15 months of age, 92% (23 of 25) mutant females developed sex cord-stromal ovarian tumors of the Sertoli-Leydig cell type, not observed in mutants at 2-5 months or in wild-type females at any age
• the remaining two mutants had atrophic ovaries with no macroscopic signs of tumorigenesis or cysts
• 91% of ovarian neoplasia was confined to a single ovary; the remaining 9% involved both ovaries
• 74% of ovarian tumors were unilateral and confined exclusively to the right ovary while 17% were confined to the left ovary
• the mean weight of the right ovary with tumor or cyst was ~36 mg while the mean weight of the left affected ovary was ~24.7 mg
• the affected ovary was enlarged 12-16 times at the age of ~7-10 months
• some ovarian tumors showed an equal admixture of tubular structures (Sertoli cells) and vacuolated plump stromal cells (Leydig cells); others were nearly devoid of tubular elements, consisting almost entirely of clusters of Leydig type cells; a focal microfollicular change in neoplastic cells, reminiscent of granulosa cells, was occasionally observed
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growth/size/body
ovary cyst
(
J:70933
)
|
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• by 12-15 months of age, 2 of the 23 tumor bearing females developed large ovarian cysts, not observed in mutants at 2-5 months or in wild-type females at any stage
• all ovarian cysts were confined to the right ovaries
• in a few ovaries, cysts were lined by a columnar epithelium with occasional vacuoles, with subjacent stroma containing vacuolated plump cells; epithelial cells ranged from a single cell-lining to a stratified cell population thrown into papillary folds
• one cyst displayed a transition from a simple columnar epithelium to a stratified epithelium with a papillary configuration
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weight loss
(
J:70933
)
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• at time of death, tumor-bearing mutants are markedly smaller, with a ~50% reduction in body weight relative to their peak weight at 10 months
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• by ~15 months, mutant females display signs of cachexia associated with advanced stages of ovarian neoplasia
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• at 3-4 months of age, the body weights of mutant females are 20% higher than those of wild-type controls
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• the tendency towards female obesity increases progressively up to ~10 months and is followed by a steady decline thereafter
(J:70933)
• by ~15 months of age, mutant females are leaner than wild-type females
(J:70933)
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• at 3-4 months of age, mutant females show a definite tendency toward obesity
(J:65577)
• in contrast to females, obesity is not observed in mutant males at any age, despite a reduction in testosterone levels
(J:65577)
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• by ~15 months, tumor-bearing mutant females display splenomegaly, not observed in age-matched wild-type females
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skeleton
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• at 4-5 months of age, the absolute weight of femur or its weight per 100 g of body weight is signicifantly reduced in mutant females relative to wild-type controls
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• at 4-5 months, x-ray analysis of the skeleton indicates an obvious hump in the upper thoracic vertebrae of mutant females
• this deformity becomes exacerbated with aging such that by 1 yr there may be as much as 10% vertebral compression resulting in a sharp bending of the spinal column
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• starting at ~4-5 months of age, all mutants display a stooped posture-kyphosis (aka dowager's hump)
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• at 4-5 months of age, x-ray analysis shows significant bone loss in the distal methaphysis of the cancellous bone of the mutant femur
• reduced radiopacity is primarily observed in the epiphyseal and metaphyseal bone areas
• histological analysis of femoral sections confirm the marked loss of trabecular bone
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homeostasis/metabolism
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• at P70, male homozygotes show a significant reduction in serum testosterone levels relative to both wild-type and heterozygous controls
• however, normal serum testosterone levels are maintained up to P70
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• at 1 yr of age, mutant circulating testosterone levels are 2-fold higher relative to age-matched wild-type females but not as exaggerated as at 3- or at 4-5-months of age
(J:70933)
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• in marked contrast to estrogen and progesterone levels, mutant serum testosterone levels are increased ~10-fold in mutant females relative to wild-type controls
(J:65577)
• following ovariectomy, testosterone disappears from circulation within 4 days
(J:65577)
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• at 3- and 12-15-months of age, mutant plasma levels of estradiol are significantly lower than wild-type levels
(J:70933)
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• at 3-4 months of age, sensitive RIAs indicate a near complete reduction (> 95%) of circulating estradiol-17beta in all mutant females
(J:65577)
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• at 3-4 months of age, mutant serum progesterone levels are reduced by 70% relative to wild-type controls (0.8 vs. 2.8 ng/ml)
• in the mutant uterus, each form of the progesterone receptor, PR-A and PR-B, is decreased by 60% relative to wild-type controls, as quantitated by densitometry
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• at 3-, 7-, and 12-15 months of age, mutant pituitary FSH content is significantly higher than wild-type; however, an age-dependent increase is observed in both genotypes, with the highest levels noted at 12-15 months
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• at 3-, 7-, and 12-15 months of age, mutant circulating FSH levels are significantly higher than wild-type levels
• at >12 months of age, mutant plasma FSH levels are increased ~3- to 4-fold relative to FSH levels in age-matched wild-type females
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• pituitary LH content is significantly increased starting at 7 months and remains high at 1 yr
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• at 3-, 7-, and 12-15 months of age, mutant circulating LH levels are significantly increased relative to wild-type levels
• at >12 months of age, mutant plasma LH levels are increased ~3- to 4-fold relative to LH levels in age-matched wild-type females
• although mutant plasma LH decline significantly after 7 months, they are still significantly higher than wild-type levels at 12-15 months of age
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calcinosis
(
J:70933
)
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• by 12 months of age, nonaffected ovaries of mutant females display multiple areas of calcification
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adipose tissue
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• at 3-4 months of age, almost all female mutants exhibit increased deposition of abdominal fat
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• at 3-4 months of age, the total weight of mutant adipose tissue including abdominal, inguinal, and retroperitoneal fat pads is increased ~2-fold relative to wild-type (600 mg vs. 335 mg)
• notably, estradiol-17beta administration reverses the accumulation of adipose tissue in mutant females, with a greater reduction of fat mass in mutant relative to wild-type control mice (66% vs 48%, respectively)
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neoplasm
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• by 12-15 months of age, 92% (23 of 25) mutant females developed sex cord-stromal ovarian tumors of the Sertoli-Leydig cell type, not observed in mutants at 2-5 months or in wild-type females at any age
• the remaining two mutants had atrophic ovaries with no macroscopic signs of tumorigenesis or cysts
• 91% of ovarian neoplasia was confined to a single ovary; the remaining 9% involved both ovaries
• 74% of ovarian tumors were unilateral and confined exclusively to the right ovary while 17% were confined to the left ovary
• the mean weight of the right ovary with tumor or cyst was ~36 mg while the mean weight of the left affected ovary was ~24.7 mg
• the affected ovary was enlarged 12-16 times at the age of ~7-10 months
• some ovarian tumors showed an equal admixture of tubular structures (Sertoli cells) and vacuolated plump stromal cells (Leydig cells); others were nearly devoid of tubular elements, consisting almost entirely of clusters of Leydig type cells; a focal microfollicular change in neoplastic cells, reminiscent of granulosa cells, was occasionally observed
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limbs/digits/tail
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• at 4-5 months of age, the absolute weight of femur or its weight per 100 g of body weight is signicifantly reduced in mutant females relative to wild-type controls
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hematopoietic system
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• by ~15 months, tumor-bearing mutant females display splenomegaly, not observed in age-matched wild-type females
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• at ~4 months of age, mutants display a significant increase in the percentage of pre B-lymphocytes in the bone marrow
• the percentage of B220-positive cells is significantly increased in mutant mice relative to wild-type controls (37% vs. 26%, respectively)
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immune system
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• by ~15 months, tumor-bearing mutant females display splenomegaly, not observed in age-matched wild-type females
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• at ~4 months of age, mutants display a significant increase in the percentage of pre B-lymphocytes in the bone marrow
• the percentage of B220-positive cells is significantly increased in mutant mice relative to wild-type controls (37% vs. 26%, respectively)
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integument
cellular
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• total sperm numbers in mutant cauda epididymides are 26%-45% lower than those of controls
• numbers of mutant sperm subclassified as motile, progressive, rapid, medium or slow are also reduced by 27%-35%
|
|
|
• ~20%-30% of mutant sperm heads and tails are abnormal relative to wild-type
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|
|
• some cross section of mutant sperm tails display a double axoneme and associated structures enveloped by a common cytoplasm
|
|
|
• some mutant sperm heads are associated with a moderately dense amorphous material
• some mutant sperm heads include large masses of cytoplasm, containing large vacuoles, membranous whorls, aggregations of mitochondria, and occasionally cross sectional profiles of tails
|
|
|
• at times, mutant acrosomes appear to be peeling off the nucleus
|
|
|
• the nuclei of mutant sperm heads are often distorted or lobulated
• in some cases, more than one nucleus are found in a common cytoplasm
|
|
|
• at P21, only a few, if any, round spermatids are observed in some mutant seminiferous tubules
• at P35, no elongating spermatids (step 11-13) are observed, unlike in wild-type and heterozygous controls
• homogenization-resistant elongated spermatids (steps 14-16) are first detectable only by P42; however, significantly less homogenization-resistant spermatids are noted at all test intervals, with differences (64%-87%) becoming severe from P63 onward
|
|
|
• at 12 months of age, male homozygotes show a 20% increase in the percentage of static sperm relative to wild-type males
• mutant sperm velocities (VAP, VSL, and VCL) and the amplitude of the lateral head displacements (ALH) are slightly but significantly lower than wild-type
• however, the beat cross frequency, head elongation ratio of sperm, and various other relative ratios (STR and LIN) remain normal
|
|
|
• the ratio of 4C:2C (where 4C = primary spermatocytes and G2 spermatogonia and 2C = spermatogonia and testicular somatic cells) is significantly reduced relative to wild-type and heterozygous controls at all age groups tested, suggesting a reduction in the % of cells undergoing spermatogonial proliferation
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