title: Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan.
abstract: A unique feature of female germ cell development in mammals is their remarkably long arrest at the prophase of meiosis I, which lasts up to 50 years in humans. Both dormant and growing oocytes are arrested at prophase I and completely lack the ability to resume meiosis. Here, we show that the prolonged meiotic arrest of female germ cells is largely achieved via the inhibitory phosphorylation of Cdk1 (cyclin-dependent kinase 1). In two mouse models where we have introduced mutant Cdk1T14AY15Fwhich cannot be inhibited by phosphorylation (Cdk1AF) in small meiotically incompetent oocytes, the prophase I arrest is interrupted, leading to a premature loss of female germ cells. We show that in growing oocytes, Cdk1AF leads to premature resumption of meiosis with condensed chromosomes and germinal vesicle breakdown followed by oocyte death, whereas in dormant oocytes, Cdk1AF leads to oocyte death directly, and both situations damage the ovarian reserve that maintains the female reproductive lifespan, which should be around 1 year in mice. Furthermore, interruption of the inhibitory phosphorylation of Cdk1 results in DNA damage, which is accompanied by induction of the Chk2 (checkpoint kinase 2)-p53/p63-dependent cell death pathway, which eventually causes global oocyte death. Together, our data demonstrate that the phosphorylation-mediated suppression of Cdk1 activity is one of the crucial factors that maintain the lengthy prophase arrest in mammalian female germ cells, which is essential for preserving the germ cell pool and reproductive lifespan in female mammals.
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg SE-405 30, Sweden.|Current address: Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria 3800, Australia.
authors: Deepak
authors: D
authors: Adhikari
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors: Kiran
authors: K
authors: Busayavalasa
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors: Jingjing
authors: J
authors: Zhang
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors: Mengwen
authors: M
authors: Hu
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors: Sanjiv
authors: S
authors: Risal
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors: Mustafa Bilal
authors: MB
authors: Bayazit
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors: Meenakshi
authors: M
authors: Singh
authors: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos #3-09, Singapore 138673, Republic of Singapore.|Current address: Izmir Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey.
authors: M Kasim
authors: MK
authors: Diril
authors: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos #3-09, Singapore 138673, Republic of Singapore.|Department of Biochemistry, National University of Singapore (NUS), Singapore 117597, Republic of Singapore.
authors: Philipp
authors: P
authors: Kaldis
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors: Kui
authors: K
authors: Liu
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D055429:Growth Differentiation Factor 9 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D049469:Meiotic Prophase I; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D012098:Reproduction / Q000502:physiology*; D000072216:Zona Pellucida Glycoproteins / Q000235:genetics / Q000378:metabolism
chemical_list: C525898:Gdf9 protein, mouse; D055429:Growth Differentiation Factor 9; D006657:Histones; D000072216:Zona Pellucida Glycoproteins; C000606521:Zp3 protein, mouse; C475961:gamma-H2AX protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D016203:CDC2 Protein Kinase