Mice Deficient in the Serine/Threonine Protein Kinase VRK1 Are Infertile Due to a Progressive Loss of Spermatogonia1

Abstract

The VRK1 protein kinase has been implicated as a pro-proliferative factor. Genetic analyses of mutant alleles of the Drosophila and Caenorhabditis elegans VRK1 homologs have revealed phenotypes ranging from embryonic lethality to mitotic and meiotic defects with resultant sterility. Herein, we describe the first genetic analysis of murine VRK1. Two lines of mice containing distinct gene-trap integrations into the Vrk1 locus were established. Insertion into intron 12 (GT12) spared VRK1 function, enabling the examination of VRK1 expression in situ. Insertion into intron 3 (GT3) disrupted VRK1 function, but incomplete splicing to the gene trap rendered this allele hypomorphic (approximately 15% of wild-type levels of VRK1 remain). GT3/GT3 mice are viable, but both males and females are infertile. In testes, VRK1 is expressed in Sertoli cells and spermatogonia. The infertility of GT3/GT3 male mice results from a progressive defect in spermatogonial proliferation or differentiation, culminating in the absence of mitotic and meiotic cells in adult testis. These data demonstrate an important role for VRK1 in cell proliferation and confirm that the need for VRK1 during gametogenesis is evolutionarily conserved.

The kinase VRK1 is required for normal meiotic progression in mammalian oogenesis

“…Additional evidence implicating a role for VRK1 in germ cell development has also been demonstrated in the germline stem cells of Caenorhabditis elegans where a reduction in proliferation, but not an increase in apoptosis, causes the sterility defect observed in vrk-1 mutants (Gorjanacz et al, 2007;Waters et al, 2010). In mammals, VRK1 has been shown to affect germ cell proliferation in males, leading to sterility (Choi et al, 2010;Wiebe et al, 2010). Female mice lacking VRK1 function are reported to be sterile as well, but the basis for this phenotype is unknown.…”

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

“…In addition, VRK1 kinase activity is enhanced in response to DNA damage and is an early participant necessary for the formation of 53BP1 foci in response to DNA double-strand breaks induced by ionizing radiation, in both resting and dividing cells [31]. In murine gene-trap models, VRK1 deficiency results in sterility due to either meiotic defects in females or by affecting maintenance of spermatogonial stem cells prior to meiosis in males [40][41][42][43].…”

Sensitivity of the kinase activity of human vaccinia-related kinase proteins to toxic metals

“…The elimination of VRK1 in gene-trap mice has revealed that reduced levels of this kinase play an important role in meiosis, resulting in male and female sterility [47][48][49]. Also, the loss in mice of coilin, a phosphorylation target of VRK1 [50], is manifested by a sterility phenotype [51].…”