The kinase-independent functions of CDK8/19, particularly the stabilization of Cyclin C, play a crucial role in the observed phenotype in DKO mice. Cyclin C is a binding partner of CDK8/19 and has been implicated in CDK8/19-independent functions. In the DKO mice, the depletion of Cyclin C leads to significant changes in gene expression and cellular processes.
One key aspect is the impact on steroidogenesis in Leydig cells. The downregulation of key steroidogenic genes, such as Cyp17a1, Star, and Fads, is observed in Leydig cells of DKO mice. These genes are essential for testosterone production and lipid metabolism, both critical for spermatogenesis. The absence of Cyclin C destabilizes the CDK8/19-Cyclin C complex, leading to disruptions in steroid biosynthesis and hormonal activity in Leydig cells. This disruption ultimately affects spermatogenesis and male fertility in DKO mice.
Furthermore, the kinase-independent functions of CDK8/19 may also influence other cellular processes beyond steroidogenesis. The stabilization of Cyclin C by CDK8/19 is known to have implications for lipid metabolism, stress response pathways, and cell cycle regulation. These functions can impact the overall cellular environment in the testes, contributing to the observed phenotype of spermatogenesis blockage and infertility in DKO mice.