Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice
CDK8 and CDK19 paralogs are regulatory kinases associated with the transcriptional Mediator complex. We have 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 or Cdk19 KO, had an atroph...
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eLife Sciences Publications Ltd
2025-04-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Alexandra V Bruter |
| collection | DOAJ |
| description | CDK8 and CDK19 paralogs are regulatory kinases associated with the transcriptional Mediator complex. We have 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 or 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, and were likely associated with an impaired synthesis of steroids. Star and Fads 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. |
| format | Article |
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| issn | 2050-084X |
| language | English |
| publishDate | 2025-04-01 |
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| spelling | doaj-art-9f6588e41adb46dba88f7d1c24c55da42025-08-20T01:55:48ZengeLife Sciences Publications LtdeLife2050-084X2025-04-011310.7554/eLife.96465Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in miceAlexandra V Bruter0Ekaterina A Varlamova1https://orcid.org/0000-0002-8451-1216Nina I Stavskaya2Zoia G Antysheva3Vasily N Manskikh4Anna V Tvorogova5Diana S Korshunova6Alvina I Khamidullina7Marina V Utkina8Viktor P Bogdanov9Iuliia P Baikova10Alyona I Nikiforova11Eugene A Albert12Denis O Maksimov13Jing Li14Mengqian Chen15https://orcid.org/0000-0003-1706-9509Gary P Schools16Alexey V Feoktistov17Alexander A Shtil18Igor B Roninson19https://orcid.org/0000-0002-9211-1327Vladislav A Mogila20https://orcid.org/0000-0003-2398-0331Yulia Y Silaeva21Victor V Tatarskiy22https://orcid.org/0000-0002-9080-5683Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian Federation; Blokhin National Medical Research Center of Oncology, Moscow, Russian FederationCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationInstitute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationInstitute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russian FederationCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian Federation; Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationEndocrinology Research Centre, Moscow, Russian FederationLife Sciences Research Center, Moscow Institute of Physics and Technology, Dolgoprudny, Russian FederationCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationInstitute of Mitoengineering MSU, Moscow, Russian FederationLife Sciences Research Center, Moscow Institute of Physics and Technology, Dolgoprudny, Russian FederationLife Sciences Research Center, Moscow Institute of Physics and Technology, Dolgoprudny, Russian FederationDepartment of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, United StatesDepartment of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, United States; Senex Biotechnology, Inc, Columbia, United StatesDepartment of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, United StatesThe Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian FederationBlokhin National Medical Research Center of Oncology, Moscow, Russian Federation; Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationDepartment of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, United StatesInstitute of Gene Biology, Russian Academy of Sciences, Moscow, Russian Federation; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, United StatesCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian Federation; Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian Federation; Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian FederationCDK8 and CDK19 paralogs are regulatory kinases associated with the transcriptional Mediator complex. We have 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 or 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, and were likely associated with an impaired synthesis of steroids. Star and Fads 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.https://elifesciences.org/articles/96465CDK8CDK19Spermatogenesis |
| spellingShingle | 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 Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice eLife CDK8 CDK19 Spermatogenesis |
| title | Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice |
| title_full | Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice |
| title_fullStr | Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice |
| title_full_unstemmed | Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice |
| title_short | Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice |
| title_sort | knockout of cyclin dependent kinases 8 and 19 leads to depletion of cyclin c and suppresses spermatogenesis and male fertility in mice |
| topic | CDK8 CDK19 Spermatogenesis |
| url | https://elifesciences.org/articles/96465 |
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