Analysis Tools|
Allele Symbol Allele Name Allele ID |
Gcnatm1.1Dcp targeted mutation 1.1, David C Page MGI:5910931 |
||||||||||||||||||||||||
| Summary |
5 genotypes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
 N |
• at E12.5, male mice show no differences in primordial germ cell (PGC) numbers relative to wild-type males, suggesting that the observed age-dependent loss of germ cells may not have an embryonic origin
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
N |
• male mice are born in expected Mendelian ratios and exhibit normal survival up to 12 months of age
|
|
|
• males show an age-dependent loss of germ cells, starting at 3 months of age
• however, the frequency of cleaved-caspase 3-positive apoptotic germ cells is not significantly altered at 6 months of age, suggesting that meiosis can proceed normally and that spermatocytes are not cleared by apoptosis
|
|
|
• starting at 3 months of age, males show a time-dependent decrease in the number of PLZF+ undifferentiated spermatogonia (USGs) per seminiferous tubule, along with an age-dependent increase in the proportion of tubules lacking any PLZF+ USGs
• however, age-dependent loss of USGs is not driven by increased apoptosis or premature differentiation of USGs
|
|
|
• at 10 weeks of age, testes show reduced protein expression of ZBTB16/PLZF [a marker of undifferentiated spermatogonia (USGs)], suggesting that maintenance of the USG pool, which comprises spermatogonial stem cells (SSCs) and progenitor germ cells, is not preserved
• in contrast, expression of WT1 (a Sertoli cell marker) is relatively normal, suggesting that that the Sertoli cell population is unaffected
|
|
|
• males show a time-dependent increase in seminiferous tubules lacking germ cells (% of Sertoli cell-only tubules)
• starting at 3 months of age, the number of PLZF+ cells per tubule is significantly lower than in wild-type controls, whereas the % of tubules lacking any PLZF+ undifferentiated spermatogonia (USGs) is significantly increased
|
|
|
• testis weight is normal at 6 weeks of age but decreases over time, starting at 3 months of age; by 12 months of age, testis weight is reduced by ~40%
|
|
|
• testes are grossly smaller by 12 months of age
|
|
|
• although initially intact, spermatogenesis becomes compromised upon aging
|
|
|
• after 3 months of age, males show a time-dependent decrease in epididymal sperm concentration, indicating reduced sperm production upon aging
• however, seminal vesicle weight and serum testosterone levels remain unaffected up to 12 months of age, and remaining sperm are functional with no significant impact on male fertility
|
|
|
• aged undifferentiated spermatogonia (USGs) replicate less due to impaired S-phase progression
|
|
N |
• mouse embryonic stem cells (mESCs) derived from male embryos show normal sensitivity to DNA-protein crosslink-inducing agents, as indicated by normal cell survival after exposure to formaldehyde (which crosslinks a broad spectrum of proteins to DNA) or etoposide (which induces DNA-Topoisomerase 2 crosslinks)
• 2D cell cycle analysis indicates normal distribution of mESCs at each stage of the cell cycle (G1, S, and G2)
|
|
|
• males show an age-dependent loss of germ cells, starting at 3 months of age
• however, the frequency of cleaved-caspase 3-positive apoptotic germ cells is not significantly altered at 6 months of age, suggesting that meiosis can proceed normally and that spermatocytes are not cleared by apoptosis
|
|
|
• after 3 months of age, males show a time-dependent decrease in epididymal sperm concentration, indicating reduced sperm production upon aging
• however, seminal vesicle weight and serum testosterone levels remain unaffected up to 12 months of age, and remaining sperm are functional with no significant impact on male fertility
|
|
|
• starting at 3 months of age, males show a time-dependent decrease in the number of PLZF+ undifferentiated spermatogonia (USGs) per seminiferous tubule, along with an age-dependent increase in the proportion of tubules lacking any PLZF+ USGs
• however, age-dependent loss of USGs is not driven by increased apoptosis or premature differentiation of USGs
|
|
|
• males fail to show an age-dependent increase in the frequency (%) of quiescent undifferentiated spermatogonia (Ki67-negative PLZF+ USGs), unlike wild-type males
• surprisingly, >6-month-old males do not exhibit an increased % of pH3-positive PLZF+ USGs, indicating that more USGs are engaged in the cell cycle but are not dividing more frequently
• at >6 months of age, the % of CCNA2-positive PLZF+ USGs is significantly higher than in wild-type males, with no change detected at 1.5 months, suggesting an accumulation in S/G2
• moreover, the % of EdU-positive PLZF+ USGs is significantly higher at 6 months of age, suggesting that USGs specifically accumulate in the S-phase
• however, the % of gamma-H2AX-positive PLZF+ USGs and the gamma-H2AX signal intensity per USG are not changed at 1.5 or 6 months of age, suggesting that USGs are not accumulating in S-phase due to DNA breaks
|
|
|
• aged undifferentiated spermatogonia (USGs) replicate less due to impaired S-phase progression
|
|
|
• at 10 weeks of age, testes show reduced protein expression of ZBTB16/PLZF [a marker of undifferentiated spermatogonia (USGs)], suggesting that maintenance of the USG pool, which comprises spermatogonial stem cells (SSCs) and progenitor germ cells, is not preserved
• in contrast, expression of WT1 (a Sertoli cell marker) is relatively normal, suggesting that that the Sertoli cell population is unaffected
|
|
|
• males show a time-dependent increase in seminiferous tubules lacking germ cells (% of Sertoli cell-only tubules)
• starting at 3 months of age, the number of PLZF+ cells per tubule is significantly lower than in wild-type controls, whereas the % of tubules lacking any PLZF+ undifferentiated spermatogonia (USGs) is significantly increased
|
|
|
• testis weight is normal at 6 weeks of age but decreases over time, starting at 3 months of age; by 12 months of age, testis weight is reduced by ~40%
|
|
|
• testes are grossly smaller by 12 months of age
|
|
N |
• male mice exhibit normal body weight up to 12 months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
 |
• female mice are born in Mendelian ratios and exhibit normal fertility with no significant reduction in the number of follicles per ovary section at 2 and 6 months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• epididymal ducts are nearly devoid of sperm in the lumen
|
|
|
• sperm exhibit an array of abnormal head shapes consistent with failure to execute proper sperm DNA topological rearrangements necessary for full compaction
|
|
|
• diplotene spermatocytes show prematurely separated bivalents, indicating lack of chiasmata
|
|
|
• 9.2% of pachytene spermatocytes show mild asynapsis of one or a few chromosomes accompanied by DNA damage, as detected by gamma-H2AX staining, relative to 0.9% of wild-type nuclei
• despite aberrant chromatin condensation in all leptotene cells, 82% of pachytene and 89% of diplotene nuclei show normal synapsis and DNA damage resolution relative to 97% and 100% of wild-type nuclei, respectively
|
|
|
• during prophase I of meiosis, all leptotene spermatocytes (stage VII-IX) show marked premature chromatin condensation; chromatin is largely detached from the nuclear membrane, occupying only a small fraction of the nucleus
• zygotene (X-XI) spermatocytes exhibit more compact chromatin than wild-type cells; however, by pachytene, nuclei recover a nearly wild-type histological appearance
• crossover analysis in pachytene spermatocyte spreads immunostained for SYCP3 (a component of the synaptonemal complex) and MLH1 (a marker for meiotic recombination events) shows significantly fewer MLH1 foci per nucleus (21 versus 26 in wild-type nuclei), an increased % of bivalents with no MLH1 focus, and a decreased % of bivalents with two MLH1 foci
• pachytene bivalents exhibit significantly less crossover interference for chromosomes 14-19 (8.498 versus 11.274 in wild-type) and chromosomes 11-13 (9.479 versus in 11.037 wild-type), as determined by the gamma shape parameter
• 79% of diplotene nuclei have at least one univalent chromosome pair versus 32.5% in wild-type nuclei
• abnormal diplotene spermatocytes show an average of 4 sets of univalents per nucleus versus 1.8 in wild-type nuclei; of the nuclei with at least one set of univalents, none affect only sex chromosomes, 36% affect only autosomes, and 64% affect both autosomes and sex chromosomes versus 21%, 43%, and 36%, respectively, in wild-type nuclei
• overall meiotic phenotypes (persistent DNA damage, decreased crossovers and crossover interference, and chromatin condensation defects) are consistent with an inability to process/resolve DNA-protein crosslinks (DPCs)
|
|
|
• 10 of 11 males tested fail to sire offspring
|
|
|
• male mice exhibit severe subfertility; most males are sterile
|
|
|
• epididymal ducts are nearly devoid of sperm in the lumen
|
|
|
• sperm exhibit an array of abnormal head shapes consistent with failure to execute proper sperm DNA topological rearrangements necessary for full compaction
|
|
|
• diplotene spermatocytes show prematurely separated bivalents, indicating lack of chiasmata
|
|
|
• 9.2% of pachytene spermatocytes show mild asynapsis of one or a few chromosomes accompanied by DNA damage, as detected by gamma-H2AX staining, relative to 0.9% of wild-type nuclei
• despite aberrant chromatin condensation in all leptotene cells, 82% of pachytene and 89% of diplotene nuclei show normal synapsis and DNA damage resolution relative to 97% and 100% of wild-type nuclei, respectively
|
|
|
• during prophase I of meiosis, all leptotene spermatocytes (stage VII-IX) show marked premature chromatin condensation; chromatin is largely detached from the nuclear membrane, occupying only a small fraction of the nucleus
• zygotene (X-XI) spermatocytes exhibit more compact chromatin than wild-type cells; however, by pachytene, nuclei recover a nearly wild-type histological appearance
• crossover analysis in pachytene spermatocyte spreads immunostained for SYCP3 (a component of the synaptonemal complex) and MLH1 (a marker for meiotic recombination events) shows significantly fewer MLH1 foci per nucleus (21 versus 26 in wild-type nuclei), an increased % of bivalents with no MLH1 focus, and a decreased % of bivalents with two MLH1 foci
• pachytene bivalents exhibit significantly less crossover interference for chromosomes 14-19 (8.498 versus 11.274 in wild-type) and chromosomes 11-13 (9.479 versus in 11.037 wild-type), as determined by the gamma shape parameter
• 79% of diplotene nuclei have at least one univalent chromosome pair versus 32.5% in wild-type nuclei
• abnormal diplotene spermatocytes show an average of 4 sets of univalents per nucleus versus 1.8 in wild-type nuclei; of the nuclei with at least one set of univalents, none affect only sex chromosomes, 36% affect only autosomes, and 64% affect both autosomes and sex chromosomes versus 21%, 43%, and 36%, respectively, in wild-type nuclei
• overall meiotic phenotypes (persistent DNA damage, decreased crossovers and crossover interference, and chromatin condensation defects) are consistent with an inability to process/resolve DNA-protein crosslinks (DPCs)
|
|
|
• overall, 9.2% of pachytene spermatocytes exhibit mild asynapsis and DNA damage, as detected by gamma-H2AX staining
• nuclei with gamma-H2AX anomalies show aberrant BRCA1 and ATR localization (proteins involved in the DNA damage response), indicating that damage repair and synapsis are interdependent
• 7.7% of pachytene and 6.5% of diplotene spermatocytes retain gamma-H2AX and ATR proteins throughout the nucleus even where synapsis proceeds normally, indicating persistent DNA damage
• male meiotic phenotypes are consistent with buildup of topoisomerase 2 (TOP2) DNA-protein crosslinks (DPCs)
|
|
|
• spermatocytes show defects in genome maintenance including DNA damage, aberrant chromosome condensation, and crossover defects
|
|
|
• overall, 9.2% of pachytene spermatocytes exhibit mild asynapsis and DNA damage, as detected by gamma-H2AX staining
• nuclei with gamma-H2AX anomalies show aberrant BRCA1 and ATR localization (proteins involved in the DNA damage response), indicating that damage repair and synapsis are interdependent
• 7.7% of pachytene and 6.5% of diplotene spermatocytes retain gamma-H2AX and ATR proteins throughout the nucleus even where synapsis proceeds normally, indicating persistent DNA damage
• male meiotic phenotypes are consistent with buildup of topoisomerase 2 (TOP2) DNA-protein crosslinks (DPCs)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
||
|
Citing These Resources Funding Information Warranty Disclaimer, Privacy Notice, Licensing, & Copyright Send questions and comments to User Support. |
last database update 09/30/2025 MGI 6.24 |
|
|
|
||
