All Phenotypes Fshr<tm1Saco> MGI Mouse

Phenotypes associated with this allele

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Fshr^tm1Saco/Fshr^tm1Saco	involves: 129	MGI:3810495
hm2	Fshr^tm1Saco/Fshr^tm1Saco	involves: C57BL/6	MGI:2665776
ht3	Fshr^tm1Saco/Fshr⁺	involves: 129	MGI:3810483
ht4	Fshr^tm1Saco/Fshr⁺	involves: 129T2/SvEmsJ	MGI:3811150
ht5	Fshr^tm1Saco/Fshr⁺	involves: C57BL/6	MGI:3810482

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

Abnormal sperm morphology in Fshr^tm1Saco/Fshr^tm1Saco mice

reproductive system

oligozoospermia ( J:137005 )

• 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%

teratozoospermia ( J:137005 )

• ~20%-30% of mutant sperm heads and tails are abnormal relative to wild-type

abnormal sperm axoneme morphology ( J:137005 )

• some cross section of mutant sperm tails display a double axoneme and associated structures enveloped by a common cytoplasm

abnormal sperm head morphology ( J:137005 )

• 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

detached acrosome ( J:137005 )

• at times, mutant acrosomes appear to be peeling off the nucleus

abnormal sperm nucleus morphology ( J:137005 )

• the nuclei of mutant sperm heads are often distorted or lobulated

• in some cases, more than one nucleus are found in a common cytoplasm

abnormal spermatid morphology ( J:70680 )

• 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

asthenozoospermia ( J:137005 )

• 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

abnormal spermatogonia proliferation ( J:70680 )

• 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

abnormal ovary morphology ( J:65577 , J:70933 )

• 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)

absent corpus luteum ( J:65577 , J:70933 )

(J:65577)

• at 3-5 months of age (J:70933)

absent mature ovarian follicles ( J:65577 )

impaired ovarian folliculogenesis ( 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

decreased ovary weight ( J:65577 )

• at 3-4 months of age, mutant ovarian weight is reduced by 58% relative to wild-type

increased ovarian carcinoma incidence ( J:70933 )

• 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

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

decreased Sertoli cell number ( J:70680 )

• 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

small seminiferous tubules ( J:70680 )

• 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

abnormal testis development ( J:70680 )

• male homozygotes display a delay in testicular development due to loss of FSH-receptor signaling

decreased testis weight ( J:70680 )

• 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

enlarged clitoris ( J:65577 )

• at the age of 6-7 months, all female homozygotes display clitorimegaly

abnormal uterus morphology ( J:65577 )

• at 3-4 months of age, mutant uteri are thin (thread like), estrogen deprived, and covered with unusual high amount of fat

abnormal endometrial gland morphology ( J:65577 )

• 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

myometrium hypoplasia ( J:65577 )

• at 3-4 months, myometrial hypoplasia is more pronounced in the outer layer of smooth muscle than in the inner layer

decreased uterus weight ( J:65577 )

• at 3-4 months of age, mutant uterine weight is reduced by 70% relative to wild-type

thin uterus ( J:65577 )

• at 3-4 months of age, uterine epithelium, stromal, and myometrial layers are severely reduced

uterus atrophy ( J:65577 )

• 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

abnormal vagina epithelium morphology ( J:65577 )

• 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

abnormal vagina orifice morphology ( J:65577 )

• unlike in wild-type and heterozygous females, vaginal opening fails to occur at proestrus

decreased vagina weight ( J:65577 )

• at 3-4 months, mutant vaginal weight is reduced by 40% relative to wild-type

vagina atrophy ( J:65577 )

abnormal spermiogenesis ( J:70680 )

• 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

small caput epididymis ( J:137005 )

• 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

abnormal corpus epididymis morphology ( J:137005 )

• 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

abnormal epididymis epithelium morphology ( J:137005 )

• male homozygotes show a dramatic size reduction of the epididymal epithelium

decreased epididymis weight ( J:70680 )

• mutant epididymides are significantly lighter than wild-type from day 28 (P28) onward

• however, no significant reduction in epididymal weight are detected until P21

delayed male fertility ( J:70680 )

• 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

delayed sexual maturation ( J:70680 )

• male homozygotes display a delay in spermatogenesis and fertilizing ability as they mature

anovulation ( J:70933 )

• at 3-5 months of age

abnormal estrous cycle ( J:65577 )

• most mutant vaginal smears do not contain estrogen-induced epithelial cornified cells but are composed of leukocytes and occasional epithelial cells

absent estrous cycle ( J:65577 , J:70933 )

• 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)

female infertility ( J:70933 )

decreased litter size ( J:70680 )

• 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)

reduced male fertility ( J:70680 )

• the number of pups sired by male homozygotes is lower than that produced by wild-type males

behavior/neurological

hunched posture ( J:65577 )

• 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

endocrine/exocrine glands

abnormal endometrial gland morphology ( J:65577 )

• 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

abnormal ovary morphology ( J:65577 , J:70933 )

• 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 12 months of age, nonaffected ovaries contained neither oocytes nor any recognizable follicles; multiple areas of calcification were observed (J:70933)

absent corpus luteum ( J:65577 , J:70933 )

(J:65577)

• at 3-5 months of age (J:70933)

absent mature ovarian follicles ( J:65577 )

impaired ovarian folliculogenesis ( 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

decreased ovary weight ( J:65577 )

• at 3-4 months of age, mutant ovarian weight is reduced by 58% relative to wild-type

increased ovarian carcinoma incidence ( J:70933 )

• 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

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

• one cyst displayed a transition from a simple columnar epithelium to a stratified epithelium with a papillary configuration

decreased Sertoli cell number ( J:70680 )

• 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

small seminiferous tubules ( J:70680 )

• 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

abnormal testis development ( J:70680 )

• male homozygotes display a delay in testicular development due to loss of FSH-receptor signaling

decreased testis weight ( J:70680 )

• 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

growth/size/body

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

• one cyst displayed a transition from a simple columnar epithelium to a stratified epithelium with a papillary configuration

weight loss ( J:70933 )

• 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

cachexia ( J:70933 )

• by ~15 months, mutant females display signs of cachexia associated with advanced stages of ovarian neoplasia

increased body weight ( J:65577 )

• at 3-4 months of age, the body weights of mutant females are 20% higher than those of wild-type controls

obese ( J:65577 , J:70933 )

	• 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)
	• 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)

enlarged spleen ( J:70933 )

• by ~15 months, tumor-bearing mutant females display splenomegaly, not observed in age-matched wild-type females

skeleton

decreased femur weight ( J:65577 )

• 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

abnormal thoracic vertebrae morphology ( J:65577 )

• 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

kyphosis ( J:65577 )

• starting at ~4-5 months of age, all mutants display a stooped posture-kyphosis (aka dowager's hump)

decreased bone mineral density of femur ( J:65577 )

• 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

homeostasis/metabolism

decreased circulating testosterone level ( J:70680 )

• 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

increased circulating testosterone level ( J:65577 , J:70933 )

	• 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)
	• 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)

decreased circulating estradiol level ( J:65577 , J:70933 )

	• at 3- and 12-15-months of age, mutant plasma levels of estradiol are significantly lower than wild-type levels (J:70933)
	• at 3-4 months of age, sensitive RIAs indicate a near complete reduction (> 95%) of circulating estradiol-17beta in all mutant females (J:65577)

decreased circulating progesterone level ( J:65577 )

• 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

increased follicle stimulating hormone level ( J:70933 )

• 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

increased circulating follicle stimulating hormone level ( J:70933 )

• 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

increased luteinizing hormone level ( J:70933 )

• pituitary LH content is significantly increased starting at 7 months and remains high at 1 yr

increased circulating luteinizing hormone level ( J:70933 )

• 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

calcinosis ( J:70933 )

• by 12 months of age, nonaffected ovaries of mutant females display multiple areas of calcification

adipose tissue

abnormal abdominal fat pad morphology ( J:65577 )

• at 3-4 months of age, almost all female mutants exhibit increased deposition of abdominal fat

increased total fat pad weight ( J:65577 )

• 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)

neoplasm

increased ovarian carcinoma incidence ( J:70933 )

• 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

limbs/digits/tail

decreased femur weight ( J:65577 )

• 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

hematopoietic system

enlarged spleen ( J:70933 )

• by ~15 months, tumor-bearing mutant females display splenomegaly, not observed in age-matched wild-type females

anemia ( J:70933 )

• by ~15 months, tumor-bearing mutant females are anemic with pale extremities

increased pre-B cell number ( J:65577 )

• 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)

immune system

enlarged spleen ( J:70933 )

• by ~15 months, tumor-bearing mutant females display splenomegaly, not observed in age-matched wild-type females

increased pre-B cell number ( J:65577 )

• 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)

integument

pallor ( J:70933 )

• by ~15 months, the extremities of tumor-bearing mutants are pale

cellular

oligozoospermia ( J:137005 )

• 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%

teratozoospermia ( J:137005 )

• ~20%-30% of mutant sperm heads and tails are abnormal relative to wild-type

abnormal sperm axoneme morphology ( J:137005 )

• some cross section of mutant sperm tails display a double axoneme and associated structures enveloped by a common cytoplasm

abnormal sperm head morphology ( J:137005 )

• 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

detached acrosome ( J:137005 )

• at times, mutant acrosomes appear to be peeling off the nucleus

abnormal sperm nucleus morphology ( J:137005 )

• the nuclei of mutant sperm heads are often distorted or lobulated

• in some cases, more than one nucleus are found in a common cytoplasm

abnormal spermatid morphology ( J:70680 )

• 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

asthenozoospermia ( J:137005 )

• 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

abnormal spermatogonia proliferation ( J:70680 )

Allelic Composition	Fshr^tm1Saco/Fshr^tm1Saco
Genetic Background	involves: C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Fshr^tm1Saco mutation (0 available); any Fshr mutation (53 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

reproductive system

abnormal spermatogonia morphology ( J:61957 )

• at 3 months of age, quantitative DNA flow cytometry shows a 28% increase in mutant spermatogonia and testicular somatic cells (2C) relative to wild-type

• mutant males display a 2-fold increase in c-kit-positive 2C cells over wild-type males

small seminal vesicle ( J:50933 , J:61957 )

(J:50933)

(J:61957)

decreased seminal vesicle weight ( J:61957 )

• at 3 months of age, a 23% reduction in mutant seminal vesicle weight is observed relative to wild-type

absent corpus luteum ( J:50933 )

• at 8 weeks of age, absent corpus luteum

abnormal ovarian folliculogenesis ( J:50933 )

• block in follicular maturation resulting in female infertility

absent mature ovarian follicles ( J:50933 )

• at 8 weeks of age, absent mature Graafian follicles

• however, normal primary and secondary follicles and normal number and location of granulosa and thecal cells

impaired ovarian folliculogenesis ( J:50933 )

• blocked prior to antral follicle formation

small ovary ( J:50933 )

• at 8 weeks of age, strikingly smaller and thinner than wild-type

abnormal seminiferous tubule morphology ( J:50933 )

• at 8 weeks of age, seminiferous tubule texture is unusual (transparent and sticky) due to altered organization of type I collagen fibrils

• no significant changes in the spermatogenic wave, respective cellular associations, and shape and numbers of somatic Sertoli and Leydig cells relative to wild-type

abnormal seminiferous tubule epithelium morphology ( J:50933 , J:61957 )

• reduced thickness of the seminiferous epithelium and a smaller lumen (J:50933)

• at 3 months of age, the area (relative volume) of mutant seminiferous epithelium is significantly reduced only at stage VII (not at stage XI) of spermatogenesis relative to wild-type (J:61957)

small seminiferous tubules ( J:50933 , J:61957 )

• at 8 weeks of age, reduced tubule diameter (20%-30% volume reduction of seminiferous tubuli) is observed (J:50933)

• at 3 months of age, the mutant seminiferous tubular and luminal diameter is smaller at stages VII and XI of spermatogenesis while the interstitial space is increased relative to wild-type (J:61957)

abnormal testis size ( J:50933 )

• starting at 6-7 weeks, drastic reduction in testis size

• accessory glands (seminal vesicles, prostate, and epididymis) appear normal

small testis ( J:50933 )

decreased testis weight ( J:61957 )

• at 3 months of age, a 54% reduction in mutant testis weight is observed relative to wild-type

small uterus ( J:50933 )

• at 8 weeks of age, strikingly smaller than wild-type

thin uterus ( J:50933 )

• at 8 weeks of age, strikingly thinner than wild-type

abnormal spermatogenesis ( J:50933 , J:61957 )

• partial spermatogenic failure (J:50933)

• mutant males show a quantitative reduction in the absolute number of germ cells undergoing spermatogenesis (J:61957)

• however, the percentage of proliferating (BrdU-positive) spermatogonial cells determined by pulse labeling for 1 hr is similar to that of wild-type and heterozygous males, indicating that spermatogenesis kinetics remain unaffected (J:61957)

abnormal sperm flagellum morphology ( J:50933 , J:61957 )

• at 6-7 weeks of age, mutant males show a 29% increase in aberrant spermatozoa exhibiting abnormal and bent tails with cytoplasmic droplets (J:50933)

• at 3 months of age, in addition to a bent tail, >80% of cauda epididymal sperm from mutant males display abnormal retention of the cytoplasmic droplet in the tails of sperm (J:61957)

kinked sperm flagellum ( J:61957 )

oligozoospermia ( J:50933 )

• at 6-7 weeks of age, a 36% reduction in sperm count relative to wild-type

enlarged sperm head ( J:61957 )

• cauda epididymal sperm from mutant males display an increased head size relative to wild-type or heterozygous sperm

abnormal spermatid morphology ( J:61957 )

• at 3 months of age, quantitative DNA flow cytometry shows a 25% decrease in the percentage of mutant elongated spermatids (HC) relative to wild-type

• the absolute number of homogenization-resistant spermatids per testis is also significantly reduced

abnormal spermiogenesis ( J:61957 )

• at 3 months of age, mutant elongated spermatids exhibit a dramatic (23%) increase in propidium iodide binding suggesting reduced nuclear compaction during spermiogenesis

abnormal epididymis morphology ( J:61957 )

• at 3 months of age, the mutant epididymis is histologically normal but not all the lumina are filled with spermatozoa

abnormal caput epididymis morphology ( J:61957 )

• at 3 months of age, some tubules of the mutant caput epididymidis are devoid of sperm

small epididymis ( J:61957 )

• at 3 months of age, the mutant epididymidis tubular diameter is smaller relative to wild-type

decreased epididymis weight ( J:61957 )

• at 3 months of age, a 30% reduction in mutant epididymis weight is observed relative to wild-type

anovulation ( J:50933 )

female infertility ( J:50933 )

• females are infertile

reduced male fertility ( J:50933 , J:61957 )

• beginning at 6-7 weeks, males exhibit reduced fertility (J:50933)

(J:61957)

abnormal sperm physiology ( J:61957 )

• in vitro, cauda epididymal sperm from mutant males are susceptible to dithiothreitol-induced decondensation, suggesting inadequate condensation of sperm chromatin

• sensitive sperm chromatin structure assays indicate that sperm nuclear DNA from mutant males are susceptible to acid denaturation, reflecting poor sperm quality

asthenozoospermia ( J:50933 , J:61957 )

• at 6-7 weeks of age, a 15% reduction in spem motility relative to wild-type (J:50933)

• at 3 months of age, cauda epididymal sperm from mutant males display reduced motility (J:61957)

endocrine/exocrine glands

increased gonadotroph cell number ( J:50933 )

• female specific, drastic increase in the number of FSH-positive cells

increased thyrotroph cell number ( J:50933 )

• female specific, moderate increase in the number of TSH-positive cells

adenohypophysis hyperplasia ( J:50933 )

• starting from 4 months of age, a female-specific 20% increase in the size of the anterior lobe related to increased cell number

small seminal vesicle ( J:50933 , J:61957 )

(J:50933)

(J:61957)

decreased seminal vesicle weight ( J:61957 )

• at 3 months of age, a 23% reduction in mutant seminal vesicle weight is observed relative to wild-type

absent corpus luteum ( J:50933 )

• at 8 weeks of age, absent corpus luteum

abnormal ovarian folliculogenesis ( J:50933 )

• block in follicular maturation resulting in female infertility

absent mature ovarian follicles ( J:50933 )

• at 8 weeks of age, absent mature Graafian follicles

• however, normal primary and secondary follicles and normal number and location of granulosa and thecal cells

impaired ovarian folliculogenesis ( J:50933 )

• blocked prior to antral follicle formation

small ovary ( J:50933 )

• at 8 weeks of age, strikingly smaller and thinner than wild-type

abnormal seminiferous tubule morphology ( J:50933 )

• at 8 weeks of age, seminiferous tubule texture is unusual (transparent and sticky) due to altered organization of type I collagen fibrils

• no significant changes in the spermatogenic wave, respective cellular associations, and shape and numbers of somatic Sertoli and Leydig cells relative to wild-type

abnormal seminiferous tubule epithelium morphology ( J:50933 , J:61957 )

• reduced thickness of the seminiferous epithelium and a smaller lumen (J:50933)

• at 3 months of age, the area (relative volume) of mutant seminiferous epithelium is significantly reduced only at stage VII (not at stage XI) of spermatogenesis relative to wild-type (J:61957)

small seminiferous tubules ( J:50933 , J:61957 )

• at 8 weeks of age, reduced tubule diameter (20%-30% volume reduction of seminiferous tubuli) is observed (J:50933)

abnormal testis size ( J:50933 )

• starting at 6-7 weeks, drastic reduction in testis size

• accessory glands (seminal vesicles, prostate, and epididymis) appear normal

small testis ( J:50933 )

decreased testis weight ( J:61957 )

• at 3 months of age, a 54% reduction in mutant testis weight is observed relative to wild-type

homeostasis/metabolism

decreased circulating testosterone level ( J:50933 , J:61957 )

• approximately 65% decrease relative to wild-type (J:50933)

• at 3 months of age, mutant serum testosterone levels are reduced by 83.2% relative to wild-type levels (J:61957)

increased circulating follicle stimulating hormone level ( J:50933 )

• at 8 weeks of age, at least a 15-fold increase in adult females and a 3- to 4-fold increase in adult males

• alpha-inhibin rates reduced to ~50% of wild-type in mutant males, with no significant changes detected in females

• notably, LH and LH-receptor levels remain unchanged in male and female mutants

nervous system

increased gonadotroph cell number ( J:50933 )

• female specific, drastic increase in the number of FSH-positive cells

increased thyrotroph cell number ( J:50933 )

• female specific, moderate increase in the number of TSH-positive cells

adenohypophysis hyperplasia ( J:50933 )

• starting from 4 months of age, a female-specific 20% increase in the size of the anterior lobe related to increased cell number

cellular

abnormal sperm flagellum morphology ( J:50933 , J:61957 )

• at 6-7 weeks of age, mutant males show a 29% increase in aberrant spermatozoa exhibiting abnormal and bent tails with cytoplasmic droplets (J:50933)

• at 3 months of age, in addition to a bent tail, >80% of cauda epididymal sperm from mutant males display abnormal retention of the cytoplasmic droplet in the tails of sperm (J:61957)

kinked sperm flagellum ( J:61957 )

oligozoospermia ( J:50933 )

• at 6-7 weeks of age, a 36% reduction in sperm count relative to wild-type

enlarged sperm head ( J:61957 )

• cauda epididymal sperm from mutant males display an increased head size relative to wild-type or heterozygous sperm

abnormal spermatid morphology ( J:61957 )

• at 3 months of age, quantitative DNA flow cytometry shows a 25% decrease in the percentage of mutant elongated spermatids (HC) relative to wild-type

• the absolute number of homogenization-resistant spermatids per testis is also significantly reduced

abnormal spermatogonia morphology ( J:61957 )

• at 3 months of age, quantitative DNA flow cytometry shows a 28% increase in mutant spermatogonia and testicular somatic cells (2C) relative to wild-type

• mutant males display a 2-fold increase in c-kit-positive 2C cells over wild-type males

asthenozoospermia ( J:50933 , J:61957 )

• at 6-7 weeks of age, a 15% reduction in spem motility relative to wild-type (J:50933)

• at 3 months of age, cauda epididymal sperm from mutant males display reduced motility (J:61957)

Allelic Composition	Fshr^tm1Saco/Fshr⁺
Genetic Background	involves: 129

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Fshr^tm1Saco mutation (0 available); any Fshr mutation (53 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

mortality/aging

neonatal lethality, complete penetrance ( J:140008 )

• all pups (if any) delivered by 12-mo-old heterozygous females die within 18-48 hrs after birth

postnatal lethality, incomplete penetrance ( J:140008 )

• success at first weaning (number of surviving pups by P21) in crosses between 3-mo-old heterozygous females and wild-type males is reduced by 25% relative to age-matched wild-type females

• in crosses between 7-mo-old heterozygous females and wild-type males the index of weaning success declines to ~43% versus ~71% in age-matched wild-type controls

premature aging ( J:65577 )

• at 3-4 months of age, female heterozygotes begin to exhibit several features that are consistent with an accelerated aging process, including premature reproductive senescence by about 7 months, skeletal deformity, and late onset of obesity

early reproductive senescence ( J:65577 , J:140008 )

• female heterozygotes display premature reproductive senescence by about 7 months (J:65577)

reproductive system

abnormal female germ cell morphology ( J:140008 )

• at 3 months of age, the oocyte diameters within primordial (stage I) follicles, primary (stage II) follicles, secondary (stage III) follicles and antral follicles of heterozygous ovaries are greater than in wild-type control follicles

• notably, at 7- and 12 months, heterozygous oocyte diameters within all types of follicles are reduced relative to wild-type; however, these differences are significant only within antral follicles of 7-mo-old ovaries and within primordial follicles of 12-mo-old ovaries

absent oocytes ( J:140008 )

• by 12 months of age, the heterozygous ovary is virtually depleted of all oocytes

oocyte degeneration ( J:140008 )

• heterozygous females exhibit accelerated oocyte loss due to atresia and increased follicular cell death in the ovary

• at 7 months of age, heterozygous ovaries have lost 75% of the oocyte pool

absent corpus luteum ( J:140008 )

• by 12 months, the corpus luteum is absent

abnormal granulosa cell morphology ( J:140008 )

• at 3 months, heterozygous mutant ovaries display large numbers of atretic follicles indicating disruption of the cellular layers and pyknotic nuclei, which is typical of atretic granulosa cells

abnormal ovarian follicle number ( J:140008 )

• female heterozygotes a significant decrease in the numbers of growing follicles in their ovary

• by 12 months of age, all heterozygous ovaries are barren while wild-type ovaries retain 30% of values noted at 3 months with active folliculogenesis and hundreds of different types of follicles and corpora lutea

decreased primary ovarian follicle number ( J:140008 )

• female heterozygotes show a 50% reduction in the number of primary follicles

abnormal ovarian folliculogenesis ( J:140008 )

• at 7 months, heterozygous ovaries display pyknotic nuclei and cellular debris in the antrum of some large follicles, many of which appear abnormal

• at 7 months, some follicles contain aberrant or double oocytes while the corpus luteum is sparse

• by 12 months, very few follicles are found, the corpus luteum is absent, and most of the heterozygous ovary consists of fibroid interstitial tissue and cystic follicles

• at 3 months, apoptotic changes in the heterozygous ovary occur predominantly in preantral medium-sized follicles while in wild-type ovaries apoptosis is mostly confined to some granulosa cells of large, antral-size follicles

increased follicle recruitment ( J:140008 )

• by 7 months of age, heterozygous ovaries show an accelerated rate of follicle recruitment from the resting pool as indicated by increased numbers of developing or growing follicles

polyovular ovarian follicle ( J:140008 )

• at 7 months, some follicles contain double oocytes

increased ovary tumor incidence ( J:140008 )

• at >12 months of age, females heterozygotes exhibit ovarian tumors

ovary cyst ( J:70933 , J:140008 )

• by 15 months of age, female heterozygotes exhibit large ovarian cysts, not present in wild-type females (J:70933)

• by 12 months, cysts form the greater part of the ovarian space in some cases (J:140008)

abnormal ovary physiology ( J:140008 )

• female heterozygotes exhibit premature ovarian failure accompanied by degenerative changes, including atresia, apoptosis, and profound loss of oocytes evident by 7 months of age

early reproductive senescence ( J:65577 , J:140008 )

• female heterozygotes display premature reproductive senescence by about 7 months (J:65577)

early vaginal opening ( J:140008 )

• in female heterozygotes the age of pubertal onset occurs ~1.8 days earlier than in wild-type siblings

delayed female fertility ( J:65577 )

• F2 heterozygous females conceive later than wild-type females (at 10-12 weeks versus at 7-8 weeks, respectively)

• the interval between mating and conception gets progressively longer with each pregnancy

long gestation period ( J:140008 )

• in 1-yr-old heterozygous females the interval between establishing the vaginal plug and delivery ranges between 45 and 60 days while age-matched wild-type controls give healthy pups within 24-28 days

abnormal estrous cycle ( J:140008 )

• at 7 months long estrus cycles are interspersed with short ones, and intermittent ovulatory cycles are intermingled with acyclic periods

prolonged diestrus ( J:65577 )

abnormal estrus ( J:65577 )

absent estrous cycle ( J:140008 )

• at 7 months, only 8 of 75 heterozygous females exhibit some cyclicity; the remaining are either acyclic with only leukocytes in the smears or with smears showing persistent vaginal cornification

• cycle frequency drops steadily with age from 4.5 cycles per month at 3 months and 2.5 cycles per month at 7 months and is lost altogether by 1 yr of age

• female heterozygotes show an increased number of cycles with extended cornification at a much earlier age relative to wild-type controls

• the percentage of virgin heterozygotes cycling at 3 months (84%) is reduced to 49% at 7 months and to 0% at 12 months versus 92%, 78%, and 62%, respectively, in virgin wild-type controls

prolonged estrous cycle ( J:65577 , J:140008 )

• heterozygotes display prolonged estrous cycles due to extended diestrus and irregular estrus patterns albeit with normal vaginal cytology (J:65577)

• notably, all heterozygous females show normal signs of estrogen stimulation (full vaginal cornification) during estrus (J:65577)

• at 3 months of age, all heterozygous females show prolonged cycles (~6.2 days) due to extended diestrus versus ~4.9 day cycles in wild-type females (J:140008)

• at 7 months, the mean length of estrous cycle for heterozygous females is ~11.6 days with a range of 4-15 days versus ~5.6 day cycles with a range of 4-7 days in wild-type controls (J:140008)

• at 7 months long estrus cycles are interspersed with short ones, and intermittent ovulatory cycles are intermingled with acyclic periods (J:140008)

female infertility ( J:65577 )

• following ~6-8 births, heterozygous females undergo early reproductive senescence and can no longer conceive, whereas wild-type controls continue to breed for >14 months

reduced female fertility ( J:140008 )

• at 3 months of age, the percentage of mated heterozygous females that deliver litters is 85% relative to 96% in wild-type controls

• at 7 months, the percentage of mated heterozygous females that deliver pups is reduced to 49% versus 83% in wild-type controls

• by 12 months, this percentage is further reduced to 12% while 73% of wild-type controls continue to produce live offspring

decreased litter size ( J:65577 , J:140008 )

• heterozygous females show a >50% reduction in litter size relative to wild-type controls (J:65577)

• heterozygous females mated with wild-type males show a significantly longer time lag between mating and first litter while the number of pups in first litter is reduced by 43% and success at first weaning (pups surviving on P21) is decreased by 25% (J:65577)

• overall breeding performance is more profoundly affected in crosses among heterozygous breeders (J:65577)

• starting at 3 months of age, heterozygous females show a 33% reduction in litter size relative to wild-type littermates (J:140008)

• litter size is further reduced at 7 months (54% less), and by 12 months heterozygous females deliver an average of only 0.5 0.3 offspring that die within 18-48 hrs after birth while 73% of wild-type controls continue to produce viable offspring (J:140008)

homeostasis/metabolism

increased circulating testosterone level ( J:65577 )

• heterozygous females show slightly increased serum testosterone levels relative to wild-type controls

decreased circulating progesterone level ( J:65577 )

• heterozygous females show a 30% reduction in serum progesterone levels relative to wild-type controls

• plasma levels of estradiol also display a decreasing trend but this difference is not significant due to variations among animals

• in the heterozygous uterus, the A form of the progesterone receptor (PR-A) (-64%) is reduced more than PR-B (-44%) relative to wild-type controls

growth/size/body

ovary cyst ( J:70933 , J:140008 )

• by 15 months of age, female heterozygotes exhibit large ovarian cysts, not present in wild-type females (J:70933)

• by 12 months, cysts form the greater part of the ovarian space in some cases (J:140008)

increased body weight ( J:65577 , J:140008 )

• at 3-4 months of age, the body weights of heterozygous females are increased by 9.6% relative to wild-type controls (J:65577)

• although at weaning the average body weight of immature heterozygous females is reduced by 9%, by 7 months their average body weight (~28.3 g) is significantly higher than that of age-matched wild-type females (J:140008)

• by 12 months, the average body weight of female heterozygotes is increased by ~25% relative to wild-type controls (J:140008)

obese ( J:65577 , J:140008 )

• by 10-12 months of age, all heterozygous females become obese (J:65577)

• at 12 months, female heterozygotes are pear-shaped and show clear signs of obesity (J:140008)

skeleton

kyphosis ( J:65577 )

• at 1 year of age, female heterozygotes that show early reproductive senescence also exhibit skeletal abnormalities characterized by a severe stooped posture-kyphosis

behavior/neurological

hunched posture ( J:65577 )

• at 1 year of age, female heterozygotes that show early reproductive senescence also exhibit skeletal abnormalities characterized by a severe stooped posture

endocrine/exocrine glands

absent corpus luteum ( J:140008 )

• by 12 months, the corpus luteum is absent

abnormal granulosa cell morphology ( J:140008 )

• at 3 months, heterozygous mutant ovaries display large numbers of atretic follicles indicating disruption of the cellular layers and pyknotic nuclei, which is typical of atretic granulosa cells

abnormal ovarian follicle number ( J:140008 )

• female heterozygotes a significant decrease in the numbers of growing follicles in their ovary

decreased primary ovarian follicle number ( J:140008 )

• female heterozygotes show a 50% reduction in the number of primary follicles

abnormal ovarian folliculogenesis ( J:140008 )

• at 7 months, heterozygous ovaries display pyknotic nuclei and cellular debris in the antrum of some large follicles, many of which appear abnormal

• at 7 months, some follicles contain aberrant or double oocytes while the corpus luteum is sparse

• by 12 months, very few follicles are found, the corpus luteum is absent, and most of the heterozygous ovary consists of fibroid interstitial tissue and cystic follicles

increased follicle recruitment ( J:140008 )

• by 7 months of age, heterozygous ovaries show an accelerated rate of follicle recruitment from the resting pool as indicated by increased numbers of developing or growing follicles

polyovular ovarian follicle ( J:140008 )

• at 7 months, some follicles contain double oocytes

increased ovary tumor incidence ( J:140008 )

• at >12 months of age, females heterozygotes exhibit ovarian tumors

ovary cyst ( J:70933 , J:140008 )

• by 15 months of age, female heterozygotes exhibit large ovarian cysts, not present in wild-type females (J:70933)

• by 12 months, cysts form the greater part of the ovarian space in some cases (J:140008)

abnormal ovary physiology ( J:140008 )

• female heterozygotes exhibit premature ovarian failure accompanied by degenerative changes, including atresia, apoptosis, and profound loss of oocytes evident by 7 months of age

neoplasm

increased ovary tumor incidence ( J:140008 )

• at >12 months of age, females heterozygotes exhibit ovarian tumors

cellular

abnormal female germ cell morphology ( J:140008 )

absent oocytes ( J:140008 )

• by 12 months of age, the heterozygous ovary is virtually depleted of all oocytes

oocyte degeneration ( J:140008 )

• heterozygous females exhibit accelerated oocyte loss due to atresia and increased follicular cell death in the ovary

• at 7 months of age, heterozygous ovaries have lost 75% of the oocyte pool

increased apoptosis ( J:140008 )

• as early as 3 months of age, TUNEL staining indicates that antral and many preantral ovarian follicles undergo apoptosis

• the percentage of degenerating preantral follicles is significantly higher in heterozygous females relative to wild-type controls (15% versus 4.3%, respectively)

Allelic Composition	Fshr^tm1Saco/Fshr⁺
Genetic Background	involves: 129T2/SvEmsJ

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Fshr^tm1Saco mutation (0 available); any Fshr mutation (53 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

mortality/aging

premature aging ( J:89713 )

• female heterozygotes exhibit premature biological aging

early reproductive senescence ( J:81460 , J:89713 )

• female heterozygotes fail to reproduce after 8-9 months of age ("retired breeders") due to an accelerated loss of ovarian function/oocytes (J:81460)

• female heterozygotes (dubbed "menopausal" mice) exhibit premature reproductive senescence mimicking reproductive failure in postmenopausal women (J:89713)

reproductive system

uterine hemorrhage ( J:81460 )

• aging female heterozygotes sometimes display uterine bleeding as the first sign of uterine pathology

• in areas of hemorrhage, hemosiderin, a golden-yellow to brown granular pigment, is phagocytized by macrophages

abnormal ovary morphology ( J:89713 )

• at 20 months of age, heterozygous ovaries are atrophic and contain no follicles or corpora lutea but only cysts

absent corpus luteum ( J:89713 )

• at 20 months of age

absent ovarian follicles ( J:89713 )

• total exhaustion of ovarian follicles at 20 months of age

ovary atrophy ( J:89713 )

• at 20 months of age

ovary cyst ( J:81460 , J:89713 )

• older virgin heterozygous females bearing a nodular uterine neoplasm in the right uterine horn may also display an ovarian cyst on the contralateral side (J:81460)

• at 20 months of age (J:89713)

early reproductive senescence ( J:81460 , J:89713 )

• female heterozygotes fail to reproduce after 8-9 months of age ("retired breeders") due to an accelerated loss of ovarian function/oocytes (J:81460)

• female heterozygotes (dubbed "menopausal" mice) exhibit premature reproductive senescence mimicking reproductive failure in postmenopausal women (J:89713)

abnormal uterus morphology ( J:81460 )

• at 12 months of age, heterozygous females display an abnormally enlarged uterus with hyperplastic and disorganized luminal epithelium and numerous blood vessels in the uterine stroma suggesting acceleration of angiogenesis

• up to 25% of virgin heterozygous females develop a variable uterine pathology, including cyst-like structures and enlarged lumen, abundant small vessels in the endometrium, adenomyosis, dilated endometrial vessels without thrombosis but associated with hemosiderin containing macrophages, and (in some cases) large uterine masses that resemble organized thrombi composed of red blood cells and fibrin along with increased angiogenesis in the stroma next to the thrombus

• most retired breeders develop larger unilateral uterine masses with varying degrees of thrombi in the outer myometrium of the affected (right) horn, regions of calcification localized in vessels near the myometrium, giant multinucleated cells similar to syncytiotrophoblasts and mononuclear cells resembling cytotrophoblasts, and increased uterine angiogenesis

enlarged endometrial glands ( J:81460 )

• at 12 months of age, endometrial glands are enlarged and the epithelia are hypertrophied

uterus cyst ( J:81460 )

• at 12 months of age, uterine transverse sections reveal the presence of cyst-like structures

increased uterus tumor incidence ( J:81460 )

• by 12 months of age, 23% of virgin heterozygous females and 82% of retired heterozygous female breeders display a large nodular structure (mass) in one uterine horn

• unilateral uterine masses occur predominantly in the right horn (67% of cases), while the left horn remains relatively unaffected

• among different female heterozygotes, the weight of the uterine nodular structure alone ranges from 205 mg to >4000 mg (~8% of the body weight) in extreme cases

enlarged uterus ( J:81460 )

• at 12 months of age

increased uterus weight ( J:81460 )

• by 1 yr of age, heterozygous females with no visible tumors show a 77% increase in uterine weight relative to wild-type females

uterus adenomyosis ( J:81460 )

• some older virgin heterozygous females have endometrial glands and stroma present within the myometrium with no connection to the endometrial cavity

absent estrous cycle ( J:81460 )

• by 12 months of age, most female heterozygotes exhibit highly irregular or absent estrous cycles

abnormal uterine environment ( J:81460 )

• at 8-10 months of age, the % of resorbed pups per pregnancy is significantly increased relative to wild-type controls (12% vs 7% at 10 dpc and 90% vs 18% at 18 dpc, respectively)

• at 10-13 months of age, the % of resorbed pups is further increased, with a fetal resorption rate of 92% at 14 dpc and >92% at 18 dpc vs only ~40% in wild-type controls

• overall, female heterozygotes show a significantly higher rate of pregnancy failure relative to wild-type females

• interestingly, structures resembling fetal tissue persist (or reappear) several months after a failed pregnancy

• pregnancy failure and induction of uterine pathology are associated with an imbalance of progesterone receptor isoforms A and B and an increase in LH receptors in the uterus along with increased angiogenesis, vascular abnormalities, and adenomyosis occuring in the uterine horn bearing the pathological mass

reduced female fertility ( J:81460 )

• as early as 3 months of age, female heterozygotes display reduced fertility relative to wild-type females

decreased litter size ( J:81460 )

• at 3 months of age, female heterozygotes produce ~40% fewer pups than wild-type females (average 5.6 vs 9.8 pups, respectively)

behavior/neurological

increased anxiety-related response ( J:89713 )

• female heterozygotes display a progressive, age-related increase in anxiety in the open field test

• at 20 months of age, female heterozygotes show a 2-fold increase in latency (time required to move from the center of the box to the wall) in an open field, relative to wild-type controls

• no significant differences in latency are observed at 1 month of age, and both heterozygous and wild-type aged mice show increased locomotor activity at 20 months

increased thigmotaxis ( J:89713 )

• at 20 months of age, female heterozygotes show increased thigmotaxis relative to wild-type controls

• however, no significant differences in thigmotaxis are observed between genotypes at 1 month of age

nervous system

abnormal dentate gyrus morphology ( J:89713 )

• in female heterozygotes, neurons in the dentate gyrus show signs of progressive degenerative changes, hypertrophy and gliosis, with subsequent cell shrinkage and death

astrocytosis ( J:89713 )

• at both 3 and 20 months of age, astroglial cells in the dentate gyrus of female heterozygotes show hypertrophic, swollen pericaria and thick processes relative to wild-type controls

neurodegeneration ( J:89713 )

• aging female heterozygotes show degenerative changes in the CNS; the region most affected is the hippocampus

hippocampal neuron degeneration ( J:89713 )

• aging female heterozygotes show altered estrogen receptor expression and significant reductions in choline acetyltransferase enzymatic activity and synapsin immunoreactivity in the hippocampus at 20 months

• early degenerative changes are evident in the hippocampus (dentate gyrus) at 1 month and progress to cell shrinkage and loss at the age of 20 months

homeostasis/metabolism

increased circulating testosterone level ( J:81460 , J:89713 )

• in heterozygous females, plasma testosterone levels are significantly higher than wild-type levels at 12 months, but not at 3 months of age (J:81460)

• female heterozygotes display higher plasma testosterone levels relative to wild-type controls, which become pronounced at 12 and 20 months of age (J:89713)

decreased circulating estradiol level ( J:81460 , J:89713 )

• in heterozygous females, plasma E2 levels are moderately reduced at proestrus at 3 months of age, and significantly reduced by 12 months of age relative to wild-type levels (J:81460)

• at 1 and 3 months of age, female heterozygotes show a moderate reduction in plasma estradiol-17beta (E2) levels relative to wild-type controls; by 7 months of age, plasma E2 levels are virtually undetectable (J:89713)

• notably, expression of nuclear estrogen receptor alpha in the amygdala of aging heterozygotes is increased, whereas expression of estrogen receptor beta in the medial amygdala is markedly reduced, possibly contributing to increased anxiogenic-like behavior (J:89713)

increased circulating follicle stimulating hormone level ( J:81460 )

• in heterozygous females, plasma FSH levels are increased by 77% relative to wild-type levels at 12 months, with no significant differences at 3 months of age

increased circulating luteinizing hormone level ( J:81460 )

• in heterozygous females, plasma LH levels are increased by 33% relative to wild-type levels at 12 months, with no significant differences at 3 months of age

decreased circulating progesterone level ( J:81460 )

• in heterozygous females, plasma progesterone levels are significantly reduced at both 3 and 12 months of age relative to wild-type levels

abnormal thrombosis ( J:81460 )

• many older virgin and retired heterozygous female breeders display dilated uterine vessels with varying degrees of thrombosis in the outer myometrium of the affected uterine horn bearing the pathological mass

abnormal enzyme/coenzyme activity ( J:89713 )

• at 20 months of age, choline acetyltransferase (ChAT) enzymatic activity is reduced by 30% in the hippocampi of female heterozygotes relative to wild-type controls

endocrine/exocrine glands

enlarged endometrial glands ( J:81460 )

• at 12 months of age, endometrial glands are enlarged and the epithelia are hypertrophied

abnormal ovary morphology ( J:89713 )

• at 20 months of age, heterozygous ovaries are atrophic and contain no follicles or corpora lutea but only cysts

absent corpus luteum ( J:89713 )

• at 20 months of age

absent ovarian follicles ( J:89713 )

• total exhaustion of ovarian follicles at 20 months of age

ovary atrophy ( J:89713 )

• at 20 months of age

ovary cyst ( J:81460 , J:89713 )

• older virgin heterozygous females bearing a nodular uterine neoplasm in the right uterine horn may also display an ovarian cyst on the contralateral side (J:81460)

• at 20 months of age (J:89713)

neoplasm

increased uterus tumor incidence ( J:81460 )

• by 12 months of age, 23% of virgin heterozygous females and 82% of retired heterozygous female breeders display a large nodular structure (mass) in one uterine horn

• unilateral uterine masses occur predominantly in the right horn (67% of cases), while the left horn remains relatively unaffected

• among different female heterozygotes, the weight of the uterine nodular structure alone ranges from 205 mg to >4000 mg (~8% of the body weight) in extreme cases

cardiovascular system

uterine hemorrhage ( J:81460 )

• aging female heterozygotes sometimes display uterine bleeding as the first sign of uterine pathology

• in areas of hemorrhage, hemosiderin, a golden-yellow to brown granular pigment, is phagocytized by macrophages

growth/size/body

ovary cyst ( J:81460 , J:89713 )

• older virgin heterozygous females bearing a nodular uterine neoplasm in the right uterine horn may also display an ovarian cyst on the contralateral side (J:81460)

• at 20 months of age (J:89713)

uterus cyst ( J:81460 )

• at 12 months of age, uterine transverse sections reveal the presence of cyst-like structures

Allelic Composition	Fshr^tm1Saco/Fshr⁺
Genetic Background	involves: C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Fshr^tm1Saco mutation (0 available); any Fshr mutation (53 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

reproductive system

abnormal male germ cell morphology ( J:61957 )

• at 3 months of age, some cauda epididymal sperm from heterozygous males display abnormal retention of the cytoplasmic droplet in the tails of sperm, not observed in wild-type males

small ovary ( J:50933 )

• at 8 weeks of age, heterozygous females show an intermediate reduction in ovary size relative to wild-type and homozygous mutant females

small uterus ( J:50933 )

• at 8 weeks of age, heterozygous females show an intermediate reduction in uterus size relative to wild-type and homozygous mutant females

abnormal spermiogenesis ( J:61957 )

• at 3 months of age, heterozygous elongated spermatids exhibit a significant (6%) increase in propidium iodide binding suggesting reduced nuclear compaction during spermiogenesis

• however, no significant differences are observed in testes, epididymal, and seminal vesicle weight, percentage of proliferating spermatogonia, testicular cell composition, or susceptibility of sperm nuclear DNA to acid denaturation relative to wild-type controls

reduced female fertility ( J:50933 )

• heterozygous females are viable but display reduced fertility relative to wild-type females

decreased litter size ( J:50933 )

• in mutants litter size is reduced by 35-50% relative wild-type mice

reduced male fertility ( J:50933 )

• heterozygous males are viable but display reduced fertility relative to wild-type males

abnormal sperm physiology ( J:61957 )

• in vitro, cauda epididymal sperm from heterozygous males are more susceptible than wild-type sperm to dithiothreitol-induced decondensation, with a significant increase in propidium iodide stainability after treatment with 2.5 and 10 mM DTT

homeostasis/metabolism

decreased circulating testosterone level ( J:50933 )

• at 8 weeks of age, heterozygous males show an intermediate reduction in serum testosterone levels relative to wild-type and homozygous mutant males

increased circulating follicle stimulating hormone level ( J:50933 )

• interestingly, at 8 weeks of age, heterozygous males (but not females) show an increase in serum FSH levels relative to wild-type controls

endocrine/exocrine glands

small ovary ( J:50933 )

• at 8 weeks of age, heterozygous females show an intermediate reduction in ovary size relative to wild-type and homozygous mutant females

cellular

abnormal male germ cell morphology ( J:61957 )

• at 3 months of age, some cauda epididymal sperm from heterozygous males display abnormal retention of the cytoplasmic droplet in the tails of sperm, not observed in wild-type males

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