Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice
Year: 2025
Type: article
Abstract: Paralogs CDK8 and CDK19 are regulatory kinases associated with the transcriptional Mediator complex. We have e generated mice with the systemic inducible Cdk8 knockout on the background of Cdk19 constitutive knockout. Cdk8/19 double knockout (iDKO) males, but not single Cdk8 and Cdk19 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 Cyp17a1, Star and Fads ) in Leydig cells concomitant with alterations in Sertoli cells and spermatocytes likely associated with impaired synthesis of steroids. Star and Fads were also downregulated in cultivated Leydig cells after iDKO. The treatment of primary Leydig cells culture with a CDK8/19 inhibitor did not induce the same changes in gene expression as iDKO, and prolonged treatment of mice with a CDK8/19 inhibitor did not affect the size of testes. iDKO, in contrast to 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.
Source: eLife
Authors: Alexandra V. Bruter, Ekaterina A. Varlamova, Nina I. Stavskaya, Zoia G. Antysheva, Vasily N. Manskikh, Anna V. Tvorogova, Diana. S. Korshunova, Alvina I. Khamidullina, Marina V. Utkina, Viktor P. Bogdanov, Iuliia P. Baikova, Alyona I. Nikiforova, Eugene A. Albert, Denis O. Maksimov, Jing Li, Mengqian Chen, Gary. P Schools, Alexey V. Feoktistov, Alexander A. Shtil, Igor B. Roninson, Vladislav A. Mogila, Yulia Y. Silaeva, Victor V. Tatarskiy
Institutions: Russian Academy of Sciences, Russian Cancer Research Center NN Blokhin, Institute of Gene Biology, Moscow Institute of Physics and Technology, Lomonosov Moscow State University, Endocrinology Research Center, Mindanao State University, Mississippi State University, University of South Carolina, Senex Biotechnology (United States), Engelhardt Institute of Molecular Biology
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W4409104910