Analysis Tools
reproductive system
 N |
• male mice exhibit normal spermatogenesis and fertility
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cellular
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Allele Symbol Allele Name Allele ID |
Tg(Ddx4-cre)1Dcas transgene insertion 1, Diego H Castrillon MGI:3757577 |
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| Summary |
33 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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N |
• male mice exhibit normal spermatogenesis and fertility
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• oligoasthenoteratozoospermia
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• lower percentage of motile sperm
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• testes contain many degenerating masses composed of fragmented spermatids and large lipid droplets
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• testes contains prominent bundles of two or more interconnected sperm
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• lower sperm counts
• cauda epididymides are almost entirely devoid of sperm but contain numerous spherical cells
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• sperm is morphologically abnormal, with 18% of sperm showing head and tail abnormalities compared to 6% of controls
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• tail defects include folded sperm or sheath abnormalities
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• defects in sperm heads include lack of the usual hook and banana-like or amorphous forms
• some sperm exhibit cavities in the sperm head
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• the numbers of spermatocytes in stages VII and VII seminiferous tubules are similar to wild-type mice, but tubules contain fewer round spermatids, indicating loss of round spermatids
• presence of large ectopic lipid droplets in round, elongating and elongated spermatids
• spermatids exhibit defects in chromatin condensation
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• males exhibit structural defects in late spermiogenesis; abnormal clustering of late spermatids of seminiferous tubules at stages VII and VIII of the seminiferous epithelial cycle , with the heads of these spermatids randomly oriented instead of being aligned perpendicular to the seminiferous tubule basement membrane
• seminiferous tubule sections near completion of spermiogenesis contain massive accumulations of spermatids in bundle-like structures
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• males exhibit normal mating behavior, however, no pregnancies or offspring are seen in breeding pairs of wild-type females and mutant males
• however, males show normal serum FSH, LH, testosterone and estradiol levels
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• oligoasthenoteratozoospermia
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• lower sperm counts
• cauda epididymides are almost entirely devoid of sperm but contain numerous spherical cells
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• sperm is morphologically abnormal, with 18% of sperm showing head and tail abnormalities compared to 6% of controls
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• tail defects include folded sperm or sheath abnormalities
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• defects in sperm heads include lack of the usual hook and banana-like or amorphous forms
• some sperm exhibit cavities in the sperm head
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• the numbers of spermatocytes in stages VII and VII seminiferous tubules are similar to wild-type mice, but tubules contain fewer round spermatids, indicating loss of round spermatids
• presence of large ectopic lipid droplets in round, elongating and elongated spermatids
• spermatids exhibit defects in chromatin condensation
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• lower percentage of motile sperm
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• testes contain many degenerating masses composed of fragmented spermatids and large lipid droplets
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N |
• males exhibit normal fasting plasma levels of cholesterol, triglycerides, and glucose and normal serum levels of insulin in a fed state
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• the relative content of phosphatidic acid is 46% higher in the testis
• elevation of phosphatidylinositol levels in the testis
• higher ratios of phosphatidic acid to phosphatidylcholine and of phosphatidic acid to phospholipid in the testis
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N |
• normal levels of adipose tissue
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• at 8 weeks of age, the number of ACRV1+ germ cells (spermatids and spermatozoa) per tubule is significantly lower than that in control testes; the protein level of acrosin (an acrosome marker) is reduced
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• at 8 weeks of age, testis weight-to-body weight ratio is significantly lower than that in control males
• however, body weight is normal
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• at 8 weeks of age, seminiferous tubules show obvious spermatogenic defects and a lower Johnsen's score, similar to Lancl1tm1.1Pfw homozygous males
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• at 8 weeks of age, caudal epididymal sperm concentration is significantly lower than that in control males
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• spermatozoa exhibit significantly increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, indicating oxidative stress
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• at 8 weeks of age, sperm forward motility (%) is significantly lower than that in control males
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• at 8 weeks of age, sperm motility (%) is significantly lower than that in control males
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• at 8 weeks of age, the number of ACRV1+ germ cells (spermatids and spermatozoa) per tubule is significantly lower than that in control testes; the protein level of acrosin (an acrosome marker) is reduced
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• at 8 weeks of age, caudal epididymal sperm concentration is significantly lower than that in control males
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• at 8 weeks of age, sperm forward motility (%) is significantly lower than that in control males
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• at 8 weeks of age, sperm motility (%) is significantly lower than that in control males
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• spermatozoa exhibit significantly increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, indicating oxidative stress
• at 8 weeks of age, testes show an increased number of gammaH2AX+ cells in the seminiferous tubules and increased protein levels of 4-hydroxy-2-nonenal (4-HNE) and BAX, indicating oxidative damage in maturing male germ cells
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• at 8 weeks of age, testis weight-to-body weight ratio is significantly lower than that in control males
• however, body weight is normal
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 7.5-fold higher than in control mice
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• 7.5-fold higher than in control mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• impairment of meiotic progression in male germ cells takes place between zygotene to pachytene stage
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• testicular weight to body weight ratio was reduced by 25% at the age of 14 month
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• impairment of meiotic progression in male germ cells takes place between zygotene to pachytene stage
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• testicular weight to body weight ratio was reduced by 25% at the age of 14 month
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• cauda epididymides are devoid of sperm
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• males show absence of all developing germ cells in the testis, presumably due to a block in mitosis
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• seminiferous tubules lack germ cells and exhibit Sertoli cell-only phenotype
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• spermatogonia are eliminated, only Sertoli cells are detected in the seminiferous epithelium
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• testes are significantly smaller than those in control males
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• cauda epididymides are devoid of sperm
• however, cauda epididymis weight is normal
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• cauda epididymides are devoid of sperm
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• males show absence of all developing germ cells in the testis, presumably due to a block in mitosis
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• seminiferous tubules lack germ cells and exhibit Sertoli cell-only phenotype
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• spermatogonia are eliminated, only Sertoli cells are detected in the seminiferous epithelium
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• testes are significantly smaller than those in control males
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• contain on average 1.5 times more cleaved caspase-3 positive tubules at 7 days post-partum compared to controls
• however, the number of apoptotic cells per tubule is similar to controls
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• display a Sertoli cell only syndrome
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• at 5 months of age
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• at 5 months of age
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• all germ cells are lost during the first wave of spermatogenesis
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• loss of germ cells and absence of sperm in the epididymis
• Sertoli cell only syndrome develops by 23 days post-partum
• expression analysis indicates misregulation of some differentiation pathways during the first wave of spermatogenesis
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• cells do not leave the basement membrane and fail to develop past the leptotene stage
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• display a Sertoli cell only syndrome
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• at 5 months of age
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• at 5 months of age
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• loss of germ cells and absence of sperm in the epididymis
• Sertoli cell only syndrome develops by 23 days post-partum
• expression analysis indicates misregulation of some differentiation pathways during the first wave of spermatogenesis
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• cells do not leave the basement membrane and fail to develop past the leptotene stage
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• contain on average 1.5 times more cleaved caspase-3 positive tubules at 7 days post-partum compared to controls
• however, the number of apoptotic cells per tubule is similar to controls
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• disorganized seminiferous epithelium
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• when expression is disrupted specifically in the male germ cells, hemizygous males have the spermatogenesis failure, sterility, small testis and disrupted seminiferous epithelium as hemizygous null males
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• disorganized seminiferous epithelium
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• complete male sterility
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• when expression is disrupted specifically in the male germ cells, hemizygous males have the spermatogenesis failure, sterility, small testis and disrupted seminiferous epithelium as hemizygous null males
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• perinatal lethality is seen in offspring from crosses between Tg(EIF1AX-Lin28a)#Gqda males with Tg(Ddx4-cre)1Dcas females (cre is expressed in oocytes)
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• 10% of offspring from crosses between Tg(EIF1AX-Lin28a)#Gqda females with Tg(Ddx4-cre)1Dcas males (cre is expressed in primordial germ cells) develop renal tumors resembling Wilms tumor
• kidneys from E18.5 mutants transplanted under the kidney capsule of immunodeficient mice results in tumor development similar to Wilms tumor
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• kidneys are larger at E18.5
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• 10% of offspring from crosses between Tg(EIF1AX-Lin28a)#Gqda females with Tg(Ddx4-cre)1Dcas males (cre is expressed in primordial germ cells) develop renal tumors resembling Wilms tumor
• kidneys from E18.5 mutants transplanted under the kidney capsule of immunodeficient mice results in tumor development similar to Wilms tumor
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• persistent proliferation of cap mesenchyme cells in adults
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• timing of kidney development is prolonged, sustaining proliferation of the cap mesenchyme cells into adulthood
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• E18.5 kidneys contain fewer mature proximal tubules
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• kidneys are larger at E18.5
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| nephroblastoma | DOID:2154 |
OMIM:194070 |
J:211179 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• less than 8% of wild-type
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• the most advanced germ cells are at the pachytene stage
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• less than 8% of wild-type
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• oocytes contain cytoplasmic RNA granules unlike in oocytes from control mice
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• at 6 months of age and beyond
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• lack of germ cells at PND25 and in adult male mice
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• fewer spermatogonia in seminiferous tubules at PND8 compared with control mice
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• ovaries lack secondary follicles
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• ovaries lack antral follicles
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• blocked at the primary follicle stage
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• ovaries lack secondary follicles
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• ovaries lack antral follicles
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• blocked at the primary follicle stage
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• oocytes contain cytoplasmic RNA granules unlike in oocytes from control mice
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• at 6 months of age and beyond
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• lack of germ cells at PND25 and in adult male mice
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• fewer spermatogonia in seminiferous tubules at PND8 compared with control mice
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• oocytes exhibit widespread m6A-dependent-splicing defects and extensive alternative polyadenylation
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• ovaries are enlarged by P21 due to global primordial follicle activation
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• ovaries explanted at birth and cultured for 8 days grow more rapidly than controls
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• ovaries are enlarged by P21 due to global primordial follicle activation
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• ovaries explanted at birth and cultured for 8 days grow more rapidly than controls
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• females exhibit a dramatic age-dependent decrease in fertility and have no more than two litters
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• ovaries are enlarged by P21 due to global primordial follicle activation
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• massive reduction in testis volume
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• severe degeneration
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• massive reduction in testis volume
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• severe degeneration
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• adult ovaries lack oocytes
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• newborn ovaries show severely impaired assembly of P-body-like granules; the mean area of DCP1A foci is reduced to 15% of that in control ovaries; however, ELAVL2 is robustly expressed in oocytes
• immunostaining of CDH1 (an oocyte marker) together with LAMININ showed direct connection between oocytes, indicating that cyst breakdown is severely impaired
• no nuclear translocation of FOXO3A is observed at P1; instead FOXO3A remains in the cytoplasm of P7 ovaries indicating that PI3K-AKT signaling is abnormally activated
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• at P7 and P21, the number of growing follicles, including follicles in the transition state, primary follicles and secondary follicles, is significantly lower than that in control ovaries
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• at P7 and P21, the number of primary ovarian follicles is severely reduced
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• at P7 and P21, the number of secondary ovarian follicles is severely reduced
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• at P21, the number of antral follicles is severely reduced
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• at P7, approximately half of the oocytes remain in cysts, unlike in control ovaries where most oocytes have developed to primordial follicles
• at P14, primordial follicles appear abnormally enlarged; the diameter of oocytes in primordial follicles is increased 1.3-fold
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• although cyst breakdown is compromised, a substantial number of primordial follicles is detected at P7
• at P21, the number of primordial follicles is severely reduced
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• no pups are born when female mice are crossed with wild-type males from 6 to 24 weeks after birth
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• adult ovaries lack oocytes
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• newborn ovaries show severely impaired assembly of P-body-like granules; the mean area of DCP1A foci is reduced to 15% of that in control ovaries; however, ELAVL2 is robustly expressed in oocytes
• immunostaining of CDH1 (an oocyte marker) together with LAMININ showed direct connection between oocytes, indicating that cyst breakdown is severely impaired
• no nuclear translocation of FOXO3A is observed at P1; instead FOXO3A remains in the cytoplasm of P7 ovaries indicating that PI3K-AKT signaling is abnormally activated
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• at P7 and P21, the number of growing follicles, including follicles in the transition state, primary follicles and secondary follicles, is significantly lower than that in control ovaries
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• at P7 and P21, the number of primary ovarian follicles is severely reduced
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• at P7 and P21, the number of secondary ovarian follicles is severely reduced
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• at P21, the number of antral follicles is severely reduced
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• at P7, approximately half of the oocytes remain in cysts, unlike in control ovaries where most oocytes have developed to primordial follicles
• at P14, primordial follicles appear abnormally enlarged; the diameter of oocytes in primordial follicles is increased 1.3-fold
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• although cyst breakdown is compromised, a substantial number of primordial follicles is detected at P7
• at P21, the number of primordial follicles is severely reduced
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• multinucleated giant cells are present in the testis cords
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• arrest at the round spermatid stage
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• multinucleated giant cells are present in the testis cords
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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N |
• females exhibit normal ovarian histology and follicle counts at 18 days (prepubertal) and at 7 months of age, indicating normal folliculogenesis
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• reduced female fertility is likely due to subtle defects in oogenesis resulting in smaller oocytes with compromised cytoplasmic competence
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• fully grown oocytes from hyperstimulated females are significantly smaller than control oocytes, as determined by germinal vesicle diameter
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• in vitro oocyte maturation (IVM) analysis revealed that only 80% of germinal vesicle-intact oocytes arrested in prophase of meiosis I are able to resume meiosis and reach metaphase of meiosis I (MI) within 8 h relative to ~90% in controls
• however, spindle morphology and chromosome alignment are normal at the MI stage and no chromosome segregation defects are observed following IVM
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• females show a mild subfertility phenotype
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• when bred with wild type male mice for 6 months, adult females produce a significantly lower average litter size than controls
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• reduced female fertility is likely due to subtle defects in oogenesis resulting in smaller oocytes with compromised cytoplasmic competence
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• fully grown oocytes from hyperstimulated females are significantly smaller than control oocytes, as determined by germinal vesicle diameter
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• in vitro oocyte maturation (IVM) analysis revealed that only 80% of germinal vesicle-intact oocytes arrested in prophase of meiosis I are able to resume meiosis and reach metaphase of meiosis I (MI) within 8 h relative to ~90% in controls
• however, spindle morphology and chromosome alignment are normal at the MI stage and no chromosome segregation defects are observed following IVM
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| N |
• in culture, the % of zygotes progressing to the blastocyst stage is not significantly different from that in controls, suggesting normal preimplantation embryo development
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• global primordial follicle activation
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• ovaries explanted at birth and cultured for 8 days grow more rapidly than controls
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• global primordial follicle activation
|
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• ovaries explanted at birth and cultured for 8 days grow more rapidly than controls
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• at 8 and 12 weeks of age
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• aberrant spermatogenic cells are seen starting at 6 weeks of age
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• few elongated spermatids are seen at 8 weeks of age
• by 12 weeks of age round spermatids are nearly absent
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• disorganized
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• testes size gradually decreases with age and by 12 weeks of age testes are significantly smaller compared to wild-type controls
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• premature release of germ cells from the seminiferous epithelium
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• males are infertile despite displaying normal mating behavior
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• at 8 and 12 weeks of age
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• aberrant spermatogenic cells are seen starting at 6 weeks of age
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• few elongated spermatids are seen at 8 weeks of age
• by 12 weeks of age round spermatids are nearly absent
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• disorganized
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• testes size gradually decreases with age and by 12 weeks of age testes are significantly smaller compared to wild-type controls
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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N |
• adult males show normal testis weight-to-body weight ratio relative to control males
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• fluorescent HSPA5 (an ER chaperone) and TO-PRO-3 (DNA) staining revealed strong HSPA5 localization within the abnormal sperm head rather than at the level of the intermediate piece as observed in wild-type sperm
• streptavidin-FITC (biotinylated proteins in mitochondria) and TO-PRO-3 (DNA) staining revealed a stronger streptavidin-FITC labeling concentrated at the abnormal sperm head, unlike in wild-type sperm
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• all cauda epididymal sperm show head distortions including abnormal heads with (i) a rather elongated head, ii) a rounded-globular head, and iii) an enlarged-deformed head
• 86% of abnormal sperm heads include types (ii) and (iii)
• normal hook-shaped sperm heads are never observed
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• fluorescent Lens culinaris agglutinin (LCA)-fluorescein isothiocyanate (FITC) (glycoconjugates) and TO-PRO-3 (DNA) staining revealed a diffuse and variable labeling of the acrosome, unlike in wild-type sperm
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• ~40% of sperm heads are rounded-globular
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• ~40% of sperm heads are enlarged and deformed
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• cauda epididymal sperm are almost immobile
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• adult males are infertile
• however, mating behavior is normal
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• fluorescent HSPA5 (an ER chaperone) and TO-PRO-3 (DNA) staining revealed strong HSPA5 localization within the abnormal sperm head rather than at the level of the intermediate piece as observed in wild-type sperm
• streptavidin-FITC (biotinylated proteins in mitochondria) and TO-PRO-3 (DNA) staining revealed a stronger streptavidin-FITC labeling concentrated at the abnormal sperm head, unlike in wild-type sperm
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• all cauda epididymal sperm show head distortions including abnormal heads with (i) a rather elongated head, ii) a rounded-globular head, and iii) an enlarged-deformed head
• 86% of abnormal sperm heads include types (ii) and (iii)
• normal hook-shaped sperm heads are never observed
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• fluorescent Lens culinaris agglutinin (LCA)-fluorescein isothiocyanate (FITC) (glycoconjugates) and TO-PRO-3 (DNA) staining revealed a diffuse and variable labeling of the acrosome, unlike in wild-type sperm
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• ~40% of sperm heads are rounded-globular
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• ~40% of sperm heads are enlarged and deformed
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• cauda epididymal sperm are almost immobile
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| male infertility due to globozoospermia | DOID:0112312 | J:168319 | ||
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• males fed a high-fat diet (HFD) for 14 weeks (to induce obesity) show a significantly lower testicular expression of BAX and cleaved-caspase-3 protein than HFD-fed wild-type males
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• males fed a HFD for 14 weeks show a significantly higher sperm forward motility (%) than HFD-fed wild-type males
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• males fed a HFD for 14 weeks show a significantly higher sperm motility (%) than HFD-fed wild-type males
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• males fed a HFD for 14 weeks show a significantly higher caudal epididymal sperm concentration than HFD-fed wild-type males
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• males fed a HFD for 14 weeks show a less distorted arrangement of germ cells in the seminiferous tubules, a better Johnsen's score, and a significantly lower teratozoospermic ratio than HFD-fed wild-type males, indicating protection from HFD/obesity-induced spermatogenic defects
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• males fed a HFD for 14 weeks show a significantly lower number of gammaH2AX+ germ cells per seminiferous tubule than HFD-fed wild-type males, indicating protection from HFD-induced oxidative damage
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• males fed a high-fat diet (HFD) for 14 weeks (to induce obesity) show a significantly lower testicular expression of BAX and cleaved-caspase-3 protein than HFD-fed wild-type males
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• males fed a HFD for 14 weeks show a significantly higher sperm forward motility (%) than HFD-fed wild-type males
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• males fed a HFD for 14 weeks show a significantly higher sperm motility (%) than HFD-fed wild-type males
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• males fed a HFD for 14 weeks show improved testicular redox imbalance with a significantly higher NADPH/NADP ratio and significantly lower malondialdehyde (MDA) and protein carbonyls in the testes than HFD-fed wild-type males, indicating protection from HFD-induced oxidative stress
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• at E10.5, mice exhibit a ventral expansion of intermediate V0, dorsal expansion of ventral V3 neurons, and reduced V1, V2, and motor neurons between them compared with control mice
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• mice exhibit normal skeleton pattern and morphology
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• at E10.5, mice exhibit a ventral expansion of intermediate V0, dorsal expansion of ventral V3 neurons, and reduced V1, V2, and motor neurons between them compared with control mice
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• in the dorsal neural tube at E10.5
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• testes show defects in spermatogonial stem cell (SSC) development
• however, testes contain normal numbers of gonocytes at birth
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• the number of undifferentiated spermatogonia (PLZF+ cells) is similar to that in controls up to P5 but significantly decreased by P7
• no GFRalpha1+ Asingle (As, early stage undifferentiated spermatogonia) or even PLZF+ undifferentiated spermatogonia are detected at 4 weeks
• however, Aaligned (Aal) spermatogonia (derived from As spermatogonia) remain, indicating that exhaustion of the SSC pool is possibly due to increased SSC proliferation
• little or no difference in apoptosis of PLZF+ spermatogonia is observed at P7
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• mice exhibit progressive loss of SSCs, causing germ cell depletion
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• at P10, EdU incorporation is significantly increased in GFRalpha1+ Asingle (As) spermatogonia (the most primitive set of spermatogonia), indicating higher proliferation of spermatogonial stem cells (SSCs)
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• by 6 weeks of age, the seminiferous tubule epithelium is completely devoid of any germ cells, with only SOX9+ Sertoli cells remaining
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• adult testes are smaller than normal
|
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|
• males are sterile
|
|
|
• testes show defects in spermatogonial stem cell (SSC) development
• however, testes contain normal numbers of gonocytes at birth
|
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|
• the number of undifferentiated spermatogonia (PLZF+ cells) is similar to that in controls up to P5 but significantly decreased by P7
• no GFRalpha1+ Asingle (As, early stage undifferentiated spermatogonia) or even PLZF+ undifferentiated spermatogonia are detected at 4 weeks
• however, Aaligned (Aal) spermatogonia (derived from As spermatogonia) remain, indicating that exhaustion of the SSC pool is possibly due to increased SSC proliferation
• little or no difference in apoptosis of PLZF+ spermatogonia is observed at P7
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• mice exhibit progressive loss of SSCs, causing germ cell depletion
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• N6-methyladenosine (m6A) levels are reduced by ~70% in THY1+ undifferentiated spermatogonia
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• at P10, EdU incorporation is significantly increased in GFRalpha1+ Asingle (As) spermatogonia (the most primitive set of spermatogonia), indicating higher proliferation of spermatogonial stem cells (SSCs)
|
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|
• mRNA m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation
|
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|
• mRNA m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation
|
|
|
• by 6 weeks of age, the seminiferous tubule epithelium is completely devoid of any germ cells, with only SOX9+ Sertoli cells remaining
|
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• adult testes are smaller than normal
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|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• at 4 weeks of age, seminiferous tubules exhibit vacuolation and disrupted arrangement of spermatogonia and primary spermatocytes
• by 8 weeks of age, fewer vacuole-like structures are found, germ cells appear disorganized, and elongated spermatozoa are absent
|
|
|
• at 4 weeks of age, seminiferous tubules exhibit vacuolation
• however, fewer vacuole-like structures are found by 8 weeks of age
|
|
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• at 4 weeks of age, testes are significantly smaller than wild-type testes
|
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• at 4 weeks of age, testes are ~20% the weight of control testes
• by 8 weeks of age, testes are ~50% the weight of control testes
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• by 8 weeks of age, testes are almost completely devoid of mature spermatozoa, as shown by H&E staining of the seminiferous tubules and epididymides
• spermatogenesis is disrupted at all levels, as germ cells are either arranged in a disorderly manner or completely absent
• no normal sperm are observed in a sperm smear collected from P56 epididymides
|
|
|
• at P38, flow cytometric analysis revealed that meiosis is blocked at the diploid stage
• surprisingly, the numbers of haploid and diploid cells are almost identical at P56, indicating that some cells can proceed to the next stage; however, any haploid cells still present at P56 appear abnormal
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• by 8 weeks of age, cauda epididymides contain some round cells of different sizes and shapes but no normal sperm
|
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• males fail to produce pups
|
|
|
• at 4 weeks of age, seminiferous tubules exhibit vacuolation and disrupted arrangement of spermatogonia and primary spermatocytes
• by 8 weeks of age, fewer vacuole-like structures are found, germ cells appear disorganized, and elongated spermatozoa are absent
|
|
|
• at 4 weeks of age, seminiferous tubules exhibit vacuolation
• however, fewer vacuole-like structures are found by 8 weeks of age
|
|
|
• at 4 weeks of age, testes are significantly smaller than wild-type testes
|
|
|
• at 4 weeks of age, testes are ~20% the weight of control testes
• by 8 weeks of age, testes are ~50% the weight of control testes
|
|
|
• at P38, flow cytometric analysis revealed that meiosis is blocked at the diploid stage
• surprisingly, the numbers of haploid and diploid cells are almost identical at P56, indicating that some cells can proceed to the next stage; however, any haploid cells still present at P56 appear abnormal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• at P8, TEM showed complete loss of spermatogonia in seminiferous tubules
|
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|
• at P12 and P60, Hematoxylin staining of seminiferous tubules showed complete germ cell loss
• at P10, no PLZF+ early spermatogonial stem cells (SSCs) are detected in seminiferous tubules
• however, GCNA+ male germ cells at still present at E18.5
|
|
|
• at P8, testes show severe depletion of germ cells in the seminiferous tubules; only SOX9+ Sertoli cells are detected at P8
|
|
|
• at P19 and P40, the number of SOX9+ Sertoli cells per tubule is significantly higher than in control testes
|
|
|
• at P40, testis size is significantly smaller than in control males
|
|
|
• from P10 to P40, testis weight is significantly lower than in control males
• however, testis weight is normal at P8
|
|
|
• at P12, seminiferous tubules display complete loss of spermatogonia and a Sertoli cell-only phenotype
• immunofluorescence staining of the Sertoli cell marker SOX9 showed that tubules only contain Sertoli cells at P8
|
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|
• at P12, seminiferous tubules show complete loss of leptotene and zygotene spermatocytes
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|
• immunofluorescence staining of meiotic markers showed no SYCP3+ or gammaH2AX+ cells in seminiferous tubules at P8
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|
• adult male mice mated with wild-type fertile females for at least 6 months produce no pups
|
|
|
• at P12, seminiferous tubules show complete loss of leptotene and zygotene spermatocytes
|
|
|
• at P8, TEM showed complete loss of spermatogonia in seminiferous tubules
|
|
|
• at P12 and P60, Hematoxylin staining of seminiferous tubules showed complete germ cell loss
• at P10, no PLZF+ early spermatogonial stem cells (SSCs) are detected in seminiferous tubules
• however, GCNA+ male germ cells at still present at E18.5
|
|
|
• immunofluorescence staining of meiotic markers showed no SYCP3+ or gammaH2AX+ cells in seminiferous tubules at P8
|
|
|
• at P8, testes show severe depletion of germ cells in the seminiferous tubules; only SOX9+ Sertoli cells are detected at P8
|
|
|
• at P19 and P40, the number of SOX9+ Sertoli cells per tubule is significantly higher than in control testes
|
|
|
• at P40, testis size is significantly smaller than in control males
|
|
|
• from P10 to P40, testis weight is significantly lower than in control males
• however, testis weight is normal at P8
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• no GFRalpha1+ Asingle (As, early stage undifferentiated spermatogonia) or PLZF+ undifferentiated spermatogonia are detected at 4 weeks
|
|
|
• double knockout mice exhibit progressive loss of spermatogonial stem cells, similar to single Mettl3em1Chhe or Mettl14em1Chhe knockouts
|
|
|
• no GFRalpha1+ Asingle (As, early stage undifferentiated spermatogonia) or PLZF+ undifferentiated spermatogonia are detected at 4 weeks
|
|
|
• double knockout mice exhibit progressive loss of spermatogonial stem cells, similar to single Mettl3em1Chhe or Mettl14em1Chhe knockouts
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• no GFRalpha1+ Asingle (As, early stage undifferentiated spermatogonia) or even PLZF+ undifferentiated spermatogonia are detected at 4 weeks
|
|
|
• mice exhibit progressive loss of spermatogonial stem cells (SSCs) causing germ cell depletion, similar to Mettl3em1Chhe/Mettl3em1Chhe Tg(Ddx4-cre)1Dcas/0 mice
|
|
|
• by 6 weeks of age, the seminiferous tubule epithelium is completely devoid of any germ cells, with only SOX9+ Sertoli cells remaining
|
|
|
• adult testes are smaller than normal
|
|
|
• no GFRalpha1+ Asingle (As, early stage undifferentiated spermatogonia) or even PLZF+ undifferentiated spermatogonia are detected at 4 weeks
|
|
|
• mice exhibit progressive loss of spermatogonial stem cells (SSCs) causing germ cell depletion, similar to Mettl3em1Chhe/Mettl3em1Chhe Tg(Ddx4-cre)1Dcas/0 mice
|
|
|
• N6-methyladenosine (m6A) levels are significantly reduced in THY1+ undifferentiated spermatogonia
|
|
|
• mRNA m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation
|
|
|
• mRNA m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation
|
|
|
• by 6 weeks of age, the seminiferous tubule epithelium is completely devoid of any germ cells, with only SOX9+ Sertoli cells remaining
|
|
|
• adult testes are smaller than normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• as in other mice carrying the conditional allele activated in oocytes by Tg(Stra8-icre)1Reb or Tg(Spo11-cre)1Rsw
|
|
|
• as in other mice carrying the conditional allele activated in oocytes by Tg(Stra8-icre)1Reb or Tg(Spo11-cre)1Rsw
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• at P6, TRA98+ spermatogonial stem cells (SSCs) are completely depleted in tubules
• at P0, numbers of TRA98+ germ cells (gonocytes) per unit area are reduced by 42%
• male germ cells are gradually lost from E18.5 to P6
|
|
|
• no sperm are released from the cauda epididymides in adult males
|
|
|
• single-cell transcriptome analysis showed that genes involved in cell cycle and glial cell line- derived neurotrophic factor (GDNF) pathway are significantly reduced in gonocytes
• at P2, testis sections show a significantly lower % of Gfra1+ gonocytes per unit area than control sections (2% versus 79%), indicating impaired gonocytes-to-spermatogonia transition
• at P2, testis sections show a significantly lower % of Ki67+ gonocytes per unit area than control sections (0.7% versus 41%), indicating impaired proliferation of gonocytes
• however, no increase in gonocyte apoptosis is detected by TUNEL staining at P0 or P2
|
|
|
• all seminiferous tubules are atrophic and empty in adult testes
• at P90, tubules are completely devoid of TRA98+ germ cells and contain only SOX9+ Sertoli cells
• at P6, TRA98+ SSCs are completely depleted in tubules, resulting in a Sertoli cell-only phenotype
|
|
|
• adult testes are significantly smaller than control testes
|
|
|
• adult testis to body weight ratio is significantly lower than that in control males
|
|
|
• adult males have no capacity to produce germ cells; no stage-specific subpopulations of spermatogenic cells are detected
• disruption of spermatogenesis occurs prior to spermatogonia formation
|
|
|
• no mature sperm are found in the cauda epididymides of adult males
|
|
|
• 3-mo-old male mice fail to produce offspring when mated with wild-type females
• however, copulatory plugs are observed
|
|
|
• at P6, TRA98+ spermatogonial stem cells (SSCs) are completely depleted in tubules
• at P0, numbers of TRA98+ germ cells (gonocytes) per unit area are reduced by 42%
• male germ cells are gradually lost from E18.5 to P6
|
|
|
• no sperm are released from the cauda epididymides in adult males
|
|
|
• single-cell transcriptome analysis showed that genes involved in cell cycle and glial cell line- derived neurotrophic factor (GDNF) pathway are significantly reduced in gonocytes
• at P2, testis sections show a significantly lower % of Gfra1+ gonocytes per unit area than control sections (2% versus 79%), indicating impaired gonocytes-to-spermatogonia transition
• at P2, testis sections show a significantly lower % of Ki67+ gonocytes per unit area than control sections (0.7% versus 41%), indicating impaired proliferation of gonocytes
• however, no increase in gonocyte apoptosis is detected by TUNEL staining at P0 or P2
|
|
|
• all seminiferous tubules are atrophic and empty in adult testes
• at P90, tubules are completely devoid of TRA98+ germ cells and contain only SOX9+ Sertoli cells
• at P6, TRA98+ SSCs are completely depleted in tubules, resulting in a Sertoli cell-only phenotype
|
|
|
• adult testes are significantly smaller than control testes
|
|
|
• adult testis to body weight ratio is significantly lower than that in control males
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• at 2 weeks of age or later, spermatogenic cells undergo apoptotic cell death at the early spermatocyte stage, as shown by TUNEL staining
• TUNEL+ spermatogenic cells are observed in the adluminal area nearest to the basal compartment throughout the postnatal to adult stages
• however, no differences in TUNEL+ cell number are observed in the newborn and 1-week-old stage
|
|
|
• at 12 weeks of age, ~85% of transverse sections of seminiferous tubules lack some spermatogenic cells
• ~3.3% of tubules contain both round and elongated spermatids but completely lack spermatocytes; ~68.8% of tubules contain a few spermatocytes and a few spermatids; and ~13.0% of tubules show almost complete lack of meiotic and post-meiotic spermatogenic cells in the adluminal compartment
|
|
|
• at 12 weeks of age, testes are grossly smaller than those in male controls
|
|
|
• at 12 weeks of age, testis weight x 100/body weight (%) is significantly lower than that in male controls
|
|
|
• testes show defective transition from the mitotic to meiotic phases and/or defective maintenance of early meiotic phase
• however, maintenance of undifferentiated GFRA1+/PLZF+ and differentiating KIT+ spermatogonia appear to be normal
|
|
|
• adult males contain only a few spermatozoa in the caudal epididymides
|
|
|
• some affected spermatids show aberrant condensed Hsc70t-positive signals as a residual body-like structure in the seminiferous tubules
• also, some elongated spermatids are degenerating and occasionally misaligned near the basement membrane, suggesting Sertoli cell phagocytosis of aberrant spermatids
|
|
|
• at 12 weeks of age, anti-SCP3 immunostaining showed that the relative number of spermatocytes is reduced to three-fourths of control testes
• however, spermatocytes that pass through meiotic differentiation and remain in affected seminiferous tubules show no defects in recombination and formation of the XY body
|
|
|
• PAS staining showed that some fully completed spermatozoa are abnormally retained in the seminiferous tubules containing the elongating spermatids at step 9-10, suggesting defects in spermiogenesis and/ or spermiation
|
|
|
• failure of spermiation subsequent to apoptotic cell death in early spermatocytes
|
|
|
• males are completely infertile
• however, vaginal plugs are observed in paired wild-type females
|
|
|
• adult males contain only a few spermatozoa in the caudal epididymides
|
|
|
• some affected spermatids show aberrant condensed Hsc70t-positive signals as a residual body-like structure in the seminiferous tubules
• also, some elongated spermatids are degenerating and occasionally misaligned near the basement membrane, suggesting Sertoli cell phagocytosis of aberrant spermatids
|
|
|
• at 12 weeks of age, anti-SCP3 immunostaining showed that the relative number of spermatocytes is reduced to three-fourths of control testes
• however, spermatocytes that pass through meiotic differentiation and remain in affected seminiferous tubules show no defects in recombination and formation of the XY body
|
|
|
• at 2 weeks of age or later, spermatogenic cells undergo apoptotic cell death at the early spermatocyte stage, as shown by TUNEL staining
• TUNEL+ spermatogenic cells are observed in the adluminal area nearest to the basal compartment throughout the postnatal to adult stages
• however, no differences in TUNEL+ cell number are observed in the newborn and 1-week-old stage
|
|
|
• at 12 weeks of age, ~85% of transverse sections of seminiferous tubules lack some spermatogenic cells
• ~3.3% of tubules contain both round and elongated spermatids but completely lack spermatocytes; ~68.8% of tubules contain a few spermatocytes and a few spermatids; and ~13.0% of tubules show almost complete lack of meiotic and post-meiotic spermatogenic cells in the adluminal compartment
|
|
|
• at 12 weeks of age, testes are grossly smaller than those in male controls
|
|
|
• at 12 weeks of age, testis weight x 100/body weight (%) is significantly lower than that in male controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
N |
• female mice exhibit normal fertility
|
|
|
• with unrepaired double strand breaks in spermatocytes
|
|
|
• arrested in pachytene
|
|
|
• with unrepaired double strand breaks in spermatocytes
|
|
|
• arrested in pachytene
|
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 07/02/2024 MGI 6.13 |
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