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We have generated mice with the systemic inducible\n                    <jats:italic>Cdk8<\/jats:italic>\n                    knockout on the background of\n                    <jats:italic>Cdk19<\/jats:italic>\n                    constitutive knockout.\n                    <jats:italic>Cdk8\/19<\/jats:italic>\n                    double knockout (iDKO) males, but not single\n                    <jats:italic>Cdk8<\/jats:italic>\n                    or\n                    <jats:italic>Cdk19<\/jats:italic>\n                    KO, had an atrophic reproductive system and were infertile. The iDKO males lacked postmeiotic spermatids and spermatocytes after meiosis I pachytene. Testosterone levels were decreased whereas the amounts of the luteinizing hormone were unchanged. Single-cell RNA sequencing showed marked differences in the expression of steroidogenic genes (such as\n                    <jats:italic>Cyp17a1, Star,<\/jats:italic>\n                    and\n                    <jats:italic>Fads<\/jats:italic>\n                    ) in Leydig cells concomitant with alterations in Sertoli cells and spermatocytes, and were likely associated with an impaired synthesis of steroids.\n                    <jats:italic>Star<\/jats:italic>\n                    and\n                    <jats:italic>Fads<\/jats:italic>\n                    were also downregulated in cultured Leydig cells after iDKO. The treatment of primary Leydig cell culture with a CDK8\/19 inhibitor did not induce the same changes in gene expression as iDKO, and a prolonged treatment of mice with a CDK8\/19 inhibitor did not affect the size of testes. iDKO, in contrast to the single knockouts or treatment with a CDK8\/19 kinase inhibitor, led to depletion of cyclin C (CCNC), the binding partner of CDK8\/19 that has been implicated in CDK8\/19-independent functions. This suggests that the observed phenotype was likely mediated through kinase-independent activities of CDK8\/19, such as CCNC stabilization.\n                  <\/jats:p>","DOI":"10.7554\/elife.96465","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T07:25:43Z","timestamp":1714548343000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.96465","source":"Crossref","is-referenced-by-count":9,"title":["Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice"],"prefix":"10.7554","volume":"13","author":[{"given":"Alexandra V","family":"Bruter","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05qrfxd25","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences","place":["Moscow, Russian 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