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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 stage. In vitro analysis of mouse spermatogonial stem cells revealed that CDKN1C localized to spindle microtubules during metaphase, and that disrupted 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 spermatogonial stem cells 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.<\/jats:p>","DOI":"10.1242\/dev.204286","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T09:03:23Z","timestamp":1737709403000},"source":"Crossref","is-referenced-by-count":2,"title":["<i>Cdkn1c<\/i> orchestrates a molecular network that regulates euploidy of male mouse germline stem cells"],"prefix":"10.1242","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0093-7501","authenticated-orcid":false,"given":"Mito","family":"Kanatsu-Shinohara","sequence":"first","affiliation":[{"name":"Graduate School of Medicine, Kyoto University 1 Department of Molecular Genetics , , Kyoto 606-8501 ,","place":["Japan"]},{"name":"AMED-CREST 2 , AMED 1-7-1 Otemachi, Chiyodaku, Tokyo 100-0004 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Center for iPS Cell Research and Application, Kyoto University 3 Department of Life Science Frontiers , , Kyoto 606-8507 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianjiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Kyoto University 1 Department of Molecular Genetics , , Kyoto 606-8501 ,","place":["Japan"]},{"name":"Chengdu Women and Children's Central Hospital 4 The Department of Gynecology , , No.1617, Riyue Avenue, Chengdu, Sichuan 610091 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi I.","family":"Nakayama","sequence":"additional","affiliation":[{"name":"TMDU Advanced Research Institute, Tokyo Medical and Dental University 5 Anticancer Strategies Laboratory , , 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Shinohara","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Kyoto University 1 Department of Molecular Genetics , , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,2,24]]},"reference":[{"key":"2025022410171125100_DEV204286C1","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.devcel.2008.01.013","article-title":"CDK inhibitors: cell cycle regulators and beyond","volume":"14","author":"Besson","year":"2008","journal-title":"Dev. 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