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

Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Biology of Reproduction (Impact Factor: 3.32). 09/2009; 82(1):182-93. DOI: 10.1095/biolreprod.109.079095
Source: PubMed


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.

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

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    • "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]. "
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    ABSTRACT: DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser-Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA-contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1-p53 basal complex is an early-warning system for immediate cellular responses to DNA damage. VRK1physically interactswithp53byanti bait coimmunoprecipitation(1,2,3,4) VRK1physically interactswithp53bypull down(1,2,3).
    FEBS letters 01/2014; 588(5). DOI:10.1016/j.febslet.2014.01.040 · 3.17 Impact Factor
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    • "When we analyzed Mena protein levels in our MenaGT/GT mice, we found that specifically in the brain, but not in other organs, the gene trap was “leaky” [27,28], resulting in a low amount of endogenous full length protein (data not shown but compare Mena protein levels in the MenaGT/GTVASP−/− organs, Figure 3A, dKO lanes). We speculated that the residual Mena expression in the brain of MenaGT/GT mice may overcome the embryonic lethal phenotype of Mena/VASP double-deficient mice and crossed the MenaGT/GT animals with our VASP−/− mice [16]. "
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    ABSTRACT: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct alphaII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and beta-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, beta-actin networks were disturbed and the integrity of Z- and intercalated discs was markedly impaired. Together, our data suggest that Mena, VASP, and alphaII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disturbed beta-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
    Cell Communication and Signaling 08/2013; 11(1):56. DOI:10.1186/1478-811X-11-56 · 3.38 Impact Factor
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    • "Moreover, recent studies have revealed that VRK1 has a function as a histone kinase that phosphorylates histone H3 (Kang et al., 2007; Baek, 2011) and it also regulates induction of cyclin D1 expression by phosphorylating CREB (Kang et al., 2008). Furthermore, studies with VRK1-deficient mice demonstrated that VRK1 is necessary for gametogenesis , spermatogonia cell maintenance, and oogenesis (Choi et al., 2010; Wiebe et al., 2010; Schober et al., 2011). Therefore the enzymatic activity of VRK1 regarding histone H3 phosphorylation must be regulated very delicately. "
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    ABSTRACT: MKP2 is a member of the dual-specificity MKPs that regulate MAPK signaling. However, MKP2 functions are still largely unknown. Here, we showed that MKP2 could regulate histone H3 phosphorylation under oxidative stress condition. We found that MKP2 inhibited histone H3 phosphorylation by suppressing VRK1 activity. Moreover, this regulation was dependent on the selective interaction with VRK1 regardless of its phosphatase activity. The interaction between MKP2 and VRK1 mainly occurred in the chromatin where histones are abundant. We also observed that the protein level of MKP2 and its interaction with histone H3 increased from G1 to M phase during the cell cycle, which is similar to the VRK1 profile. Furthermore, MKP2 specifically regulated the VRK1-mediated histone H3 phosphorylation at M phase. Taken together, we suggest a novel function of MKP2 as a negative regulator of VRK1-mediated histone H3 phosphorylation.
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