Karyotype instability in the germline leads to infertility. Unlike the female germline, the male germline continuously produces fertile sperm throughout life. Here we present a molecular network responsible for maintaining karyotype stability in the male mouse germline. Loss of the cyclin-dependent kinase inhibitor Cdkn1c in undifferentiated spermatogonia induced degeneration of spermatogenesis prior to entry into the differentiating spermatogonia. In vitro analysis of spermatogonial stem cells (SSCs) revealed that CDKN1C localized to spindle microtubules during metaphase, and that disupted microtubule dynamics increased its phosphorylation. Cdkn1c deficiency activated the spindle assembly checkpoint and led to centrosome amplification, premature chromosome segregation, and loss of AURKB, and ultimately TRP53-dependent apoptosis. Trp53-deficient SSCs exhibited karyotype defects, but proliferated normally despite reduced CDKN1C and AURKB expression. In contrast, Aurkb depletion upregulated TRP53 and CDKN1C, suggesting a negative feedback loop to maintain euploidy. Thus, Cdkn1c regulates the male germline karyotype.
Cdkn1c orchestrates a molecular network that regulates the euploidy of the male mouse germline stem cells
- Award Group:
- Funder(s): Ministry of Education, Culture, Sports, Science and Technology
- Award Id(s): 23H03036, 26293064
- Funder(s):
- Award Group:
- Funder(s): Japan Agency for Medical Research and Development
- Award Id(s): JP23gm1110008, JP24zf0127011
- Funder(s):
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Mito Kanatsu-Shinohara, Takuya Yamamoto, Tianjiao Liu, Keiichi I. Nakayama, Takashi Shinohara; Cdkn1c orchestrates a molecular network that regulates the euploidy of the male mouse germline stem cells. Development 2025; dev.204286. doi: https://doi.org/10.1242/dev.204286
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