Analysis of the role of the VRK1 protein kinase in mammalian fertility

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DESCRIPTION (provided by applicant): Gametogenesis is a highly regulated process that has profound importance for the maintenance of animal species. Errors in gametogenesis have consequences that range from infertility to the transmission of chromosome abnormalities to the next generation. However, the signaling cascades critical to both spermatogenesis and oogenesis are still poorly understood. Dynamic protein phosphorylation, mediated by protein kinases and phosphatases, is one of the major mechanisms used by eukaryotic cells to ensure that the phases of mitotic and meiotic cell division occur in the correct sequence and only when intracellular and extracellular conditions are favorable. The focus of this project is the VRK1 protein kinase, which is involved in the regulation of cell proliferation in organisms ranging from invertebrates to mammals. The VRK1 orthologs in Drosophila and C. elegans are essential proteins whose disruption causes sterility associated with meiotic defects. Recently, we have generated gene-targeted mice that are hypomorphic for the expression of VRK1. In the homozygous state, both the male and female VRK1-deficient mice are infertile, indicating that the role of VRK in fertility is evolutionarily conserved. In male mice, this infertility is associated with a severe and progressive loss of spermatogonia. In Aim 1 of this proposal, we will investigate this phenotype further and test the hypothesis that VRK1 depletion leads to a cell-autonomous defect in the proliferation and/or differentiation of spermatogonial stem cells. We will also explore the alternative hypothesis that VRK1- deficient Sertoli cells cannot provide a niche that is competent to support ongoing spermatogenesis. Female mice that are hypomorphic for VRK1 expression are also infertile; understanding how VRK1 depletion impacts female fertility will therefore be the focus of Aim 2 of this proposal. Interestingly, in contrast to the defect in males, preliminary histological analyses reveal that maturation of ovarian follicles and ovulation proceed normally in VRK-deficient mice. We therefore hypothesize that, within oocytes, VRK1 may be most critical for the resumption and completion of meiosis. Our preliminary data provides the first evidence that VRK1 plays a key role in mammalian gametogenesis. The severe infertility that results from its depletion suggests that a greater understanding of VRK1 may provide novel insights of significant relevance to human reproduction. A deeper understanding of the signaling pathways that regulate gametogenesis will provide new approaches with which to combat infertility and new targets for the development of male contraceptives. PUBLIC HEALTH RELEVANCE: Our studies of the VRK1 protein kinase and its contribution to male and female fertility have important implications for human health. Understanding how the signaling pathways mediated by VRK1 affect spermatogenesis and oogenesis will deepen our understanding of the causes of human infertility and elucidate new targets for male contraception.