Mouse Genome Informatics
hm1
    Nr0b1tm1.1Lja/Nr0b1tm1.1Lja
involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
reproductive system
• subsets of follicles contain multiple oocytes (J:51292)
• however, female homozygotes are fertile, produce normal litter sizes, with no apparent defects in sexual maturation, ovarian formation or ovulation (J:51292)

endocrine/exocrine glands
• subsets of follicles contain multiple oocytes (J:51292)
• however, female homozygotes are fertile, produce normal litter sizes, with no apparent defects in sexual maturation, ovarian formation or ovulation (J:51292)


Mouse Genome Informatics
ot2
    Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
reproductive system
• male hemizygotes display progressive loss of the germinal epithelium during postnatal testicular maturation (J:51292)
• at 12 weeks of age, the proximal and middle efferent ductules are obstructed by Sertoli cells, blocking the passage of sperm, and the epithelium of the efferent duct is frequently overgrown (J:71710)
• notably, the epithelia display numerous basally positioned lipid deposits not observed in wild-type (J:71710)
• in contrast, the mutant epididymides appear morphologically normal (J:71710)
• at 12 weeks of age, the rete testis is blocked by abnormally located Sertoli cells, creating a tailback of necrosing sperm in the testis (J:71710)
• at 12 weeks, Leydig cells in the interstitial space near the rete appear hyperplastic, with large mitochondria containing numerous tubular cristae (J:71710)
• in contrast, Leydig cells found in the seminiferous tubules are smaller and contain smaller mitochondria (J:71710)
• neither type of Leydig cell displays the cytoplasmic swirls of saccular endoplasmic reticulum typical of adult wild-type Leydig cells (J:71710)
• fetal Leydig cell development is arrested, with Leydig cells restricted to the ventral surface of the gonad (J:81356)
• at 10 weeks, interstitial Leydig cells show cellular hypertrophy and hyperplasia in the vicinity of severely degenerated seminiferous tubules (J:51292)
• at >1 yr of age, most male hemizygotes exhibit Leydig cell hyperplasia (J:71710)
• a few cases of Leydig cell neoplasia are also observed (J:71710)
• at 12 weeks of age, seminiferous tubules close to the rete testis exhibit ectopic Leydig cells, distinct from the hyperplastic Leydig cells found in the interstitial space (J:71710)
• at 13.5 dpc, Leydig cells, which normally reside in the peritubular space and extend from the coelomic surface to the dorsal surface of the gonad, are restricted to the coelomic surface and almost completely excluded from the dorsal part of the gonad (J:81356)
• at 12 weeks of age, peritubular myoid cells appear poorly differentiated (J:71710)
• no basement membrane between the myoid cells and Sertoli cells is observed (J:71710)
• at 13.5 dpc, the number of peritubular myoid cells, which normally surround the testis cords, is reduced (J:81356)
• BrdU labeling of peritubular myoid cells is low, consistent with decreased proliferation (J:81356)
• at 10 weeks of age, some tubules display thin, irregular epithelia with sloughing of germ cells into the lumen (J:51292)
• occasional tubules show active spermatogenesis with stratified germinal epithelium and a relatively normal appearance (J:51292)
• at 12 weeks of age, vacuolation of the seminiferous epithelium and lipid accumulation are common in affected tubules, especially near the rete and in all tubules in older males, indicating a breakdown in Sertoli-germ cell junctions (J:71710)
• at 12 weeks of age, the rete testis is blocked by ectopic Sertoli cells found within the lumen of the seminiferous tubules and efferent ducts (J:71710)
• adult male hemizygotes exhibit dilated seminiferous tubules at all test ages (J:71710)
• tubule dilation is transient, with marked variability in the proportions of normal, dilated, and degenerating seminiferous tubules between different males of different ages (J:71710)
• epithelial dysgenesis and degeneration exhibited at 10 weeks of age (J:51292)
• adult male hemizygotes exhibit degenerating seminiferous tubules at all test ages (J:71710)
• at 13.5 dpc, organization and differentiation of mutant Sertoli cells is decreased relative to wild-type (J:81356)
• at 12 weeks of age, abnormal proliferation of Sertoli cells results in the blockage of the rete testis and efferent ducts, impeding the passage of sperm into the epididymis (J:71710)
• at 13.5 dpc, testis cord formation is delayed, as shown by a decreased number of cords that are poorly distinguished from the peritubular space (J:81356)
• at 13.5 dpc, the coelomic vessel is still present on the ventral surface; however, the ventral-dorsal width is intermediate between male and female gonads (J:81356)
• at 13.5 dpc, germ cells and Sertoli cells cluster together within the dorsal surface of the gonad, but only a few PTM cells are observed (J:81356)
• the basal lamina which defines the edges of individual testis cords is either disrupted or absent at 12.5, 13.5 and 14.5 dpc (J:81356)
• at 14.5 dpc, testis cord-like structures are present but appear smaller, irregular in shape, and with frequent breaks in laminin localization (J:81356)
• at 13.5 dpc, testis cords appear disorganized and incompletely formed; however, the number of germ and Sertoli cells and the expression of Sertoli-specific markers appear to be normal (J:81356)
• at 14.5 dpc, testis cords remain rudimentary, with occasional scattered PTM cells present at the ventral surface, leaving the dorsal half of the gonad more disorganized (J:81356)
• by 17.5 dpc, testis cords are larger than normal and more pleomorphic in shape, without clearly defined borders (J:81356)
• male hemizygotes have small testes despite normal serum levels of testosterone and gonadotropins (J:51292)
• approximately 50% reduction in weight relative to wild-type (J:51292)
• at 12 weeks of age, mutant testes weigh significantly less than wild-type (126.2 4.9 mg vs. 212.1 18.0 mg, respectively) (J:71710)
• progressive loss of male germ cells evident at 10 weeks of age (J:51292)
• complete loss of male germ cells after 14 weeks of age (J:51292)
• spermatocytes are present at 10 weeks of age; however, germ cell depletion is observed at 14 weeks of age, indicating a defect in the maintenance of spermatogenesis (J:51292)
• however, embryonic and early postnatal testosterone production is sufficient for formation of male internal and external genitalia and testicular descent (J:51292)
• unlike female homozygotes, male hemizygotes are infertile (J:51292)
• male hemizygotes display abnormal differentiation and proliferation of Leydig cells and Sertoli cells, leading to obstruction of the rete testis and infertility (J:71710)

endocrine/exocrine glands
N
• normal zonae glomerulosa and fasciculata in adult cortical zones (J:51292)
• serum corticosterone levels were similar to those of wild-type mice, indicating normal adrenal secretion (J:51292)
• normal pituitary morphology (J:51292)
• normal serum levels of LH and FSH (J:51292)
• retention of fetal X-zone (J:51292)
• male hemizygotes display progressive loss of the germinal epithelium during postnatal testicular maturation (J:51292)
• at 12 weeks of age, the proximal and middle efferent ductules are obstructed by Sertoli cells, blocking the passage of sperm, and the epithelium of the efferent duct is frequently overgrown (J:71710)
• notably, the epithelia display numerous basally positioned lipid deposits not observed in wild-type (J:71710)
• in contrast, the mutant epididymides appear morphologically normal (J:71710)
• at 12 weeks of age, the rete testis is blocked by abnormally located Sertoli cells, creating a tailback of necrosing sperm in the testis (J:71710)
• at 12 weeks, Leydig cells in the interstitial space near the rete appear hyperplastic, with large mitochondria containing numerous tubular cristae (J:71710)
• in contrast, Leydig cells found in the seminiferous tubules are smaller and contain smaller mitochondria (J:71710)
• neither type of Leydig cell displays the cytoplasmic swirls of saccular endoplasmic reticulum typical of adult wild-type Leydig cells (J:71710)
• fetal Leydig cell development is arrested, with Leydig cells restricted to the ventral surface of the gonad (J:81356)
• at 10 weeks, interstitial Leydig cells show cellular hypertrophy and hyperplasia in the vicinity of severely degenerated seminiferous tubules (J:51292)
• at >1 yr of age, most male hemizygotes exhibit Leydig cell hyperplasia (J:71710)
• a few cases of Leydig cell neoplasia are also observed (J:71710)
• at 12 weeks of age, seminiferous tubules close to the rete testis exhibit ectopic Leydig cells, distinct from the hyperplastic Leydig cells found in the interstitial space (J:71710)
• at 13.5 dpc, Leydig cells, which normally reside in the peritubular space and extend from the coelomic surface to the dorsal surface of the gonad, are restricted to the coelomic surface and almost completely excluded from the dorsal part of the gonad (J:81356)
• at 12 weeks of age, peritubular myoid cells appear poorly differentiated (J:71710)
• no basement membrane between the myoid cells and Sertoli cells is observed (J:71710)
• at 13.5 dpc, the number of peritubular myoid cells, which normally surround the testis cords, is reduced (J:81356)
• BrdU labeling of peritubular myoid cells is low, consistent with decreased proliferation (J:81356)
• at 10 weeks of age, some tubules display thin, irregular epithelia with sloughing of germ cells into the lumen (J:51292)
• occasional tubules show active spermatogenesis with stratified germinal epithelium and a relatively normal appearance (J:51292)
• at 12 weeks of age, vacuolation of the seminiferous epithelium and lipid accumulation are common in affected tubules, especially near the rete and in all tubules in older males, indicating a breakdown in Sertoli-germ cell junctions (J:71710)
• at 12 weeks of age, the rete testis is blocked by ectopic Sertoli cells found within the lumen of the seminiferous tubules and efferent ducts (J:71710)
• adult male hemizygotes exhibit dilated seminiferous tubules at all test ages (J:71710)
• tubule dilation is transient, with marked variability in the proportions of normal, dilated, and degenerating seminiferous tubules between different males of different ages (J:71710)
• epithelial dysgenesis and degeneration exhibited at 10 weeks of age (J:51292)
• adult male hemizygotes exhibit degenerating seminiferous tubules at all test ages (J:71710)
• at 13.5 dpc, organization and differentiation of mutant Sertoli cells is decreased relative to wild-type (J:81356)
• at 12 weeks of age, abnormal proliferation of Sertoli cells results in the blockage of the rete testis and efferent ducts, impeding the passage of sperm into the epididymis (J:71710)
• at 13.5 dpc, testis cord formation is delayed, as shown by a decreased number of cords that are poorly distinguished from the peritubular space (J:81356)
• at 13.5 dpc, the coelomic vessel is still present on the ventral surface; however, the ventral-dorsal width is intermediate between male and female gonads (J:81356)
• at 13.5 dpc, germ cells and Sertoli cells cluster together within the dorsal surface of the gonad, but only a few PTM cells are observed (J:81356)
• the basal lamina which defines the edges of individual testis cords is either disrupted or absent at 12.5, 13.5 and 14.5 dpc (J:81356)
• at 14.5 dpc, testis cord-like structures are present but appear smaller, irregular in shape, and with frequent breaks in laminin localization (J:81356)
• at 13.5 dpc, testis cords appear disorganized and incompletely formed; however, the number of germ and Sertoli cells and the expression of Sertoli-specific markers appear to be normal (J:81356)
• at 14.5 dpc, testis cords remain rudimentary, with occasional scattered PTM cells present at the ventral surface, leaving the dorsal half of the gonad more disorganized (J:81356)
• by 17.5 dpc, testis cords are larger than normal and more pleomorphic in shape, without clearly defined borders (J:81356)
• male hemizygotes have small testes despite normal serum levels of testosterone and gonadotropins (J:51292)
• approximately 50% reduction in weight relative to wild-type (J:51292)
• at 12 weeks of age, mutant testes weigh significantly less than wild-type (126.2 4.9 mg vs. 212.1 18.0 mg, respectively) (J:71710)

tumorigenesis
• at >1 year of age, approximately 1/3 of male hemizygotes display bilateral testicular tumors, immunohistochemically confirmed as sex cord-stromal and not germ cell in origin (J:71710)
• these tumors are either derived from cells of the Sertoli/granulosa cell lineage or Leydig interstitial cells (J:71710)
• in both cases, the tumors cause tubular degeneration and a block of spermatogenesis and are mitotically active (J:71710)
• typically, the surrounding testicular tissue is composed of hemorrhage and fluid (J:71710)

homeostasis/metabolism
• at 12 weeks of age, male hemizygotes show significant lipid deposits in the interstitial tissue immediately adjacent to the blockage of rete testis by Sertoli cells (J:71710)
• many of the macrophages observed in interstitial tissue contain cholesterol crystalloid structures (J:71710)
• cholesterol crystals are also noted in several Leydig and Sertoli cells, suggesting a steroidogenic defect (J:71710)
• in addition, the epithelium of the efferent duct contains numerous basally positioned lipid deposits not observed in wild-type controls (J:71710)

Mouse Models of Human Disease
OMIM IDRef(s)
Adrenal Hypoplasia, Congenital; AHC 300200 J:51292 , J:71710