Deepak Adhikari1, Kiran Busayavalasa1, Jingjing Zhang1, Mengwen Hu1, Sanjiv Risal1, Mustafa Bilal Bayazit1, Meenakshi Singh1, M Kasim Diril2, Philipp Kaldis2,3,*, Kui Liu1,*
1 Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg SE-405 30, Sweden
2 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;
3 Department of Biochemistry, National University of Singapore (NUS), Singapore 117597, Republic of Singapore
Published online in Cell Research on 21 October 2016.
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 Cdk1T14AY15F which 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.
Illustrations of oocyte prophase I arrest and the strategy for expressing the Cdk1AF allele in dormant and growing oocytes. (A) All of the dormant and growing oocytes remain in prophase I arrest with GV and are meiotically incompetent. Only the fully grown oocytes are meiotically competent and have the capability of resuming meiosis. Gdf9-Cre recombinase starts to be expressed in dormant oocytes in primordial follicles, and Zp3-Cre starts to be expressed only in growing oocytes in developing follicles. GV, germinal vesicle. (B) Cdk1 remains in an inactive state due to its phosphorylation at T14 and Y15 by Wee1/Myt1. Cdk1 activation requires dephosphorylation of T14 and Y15 by Cdc25. Cdk1 with mutation of T14 and Y15 to A14 and F15 cannot be phosphorylated and therefore Cdk1 activity cannot be inhibited by Wee1/Myt1. (C) Oocyte-specific expression of the Cdk1AF allele starting from dormant oocytes as mediated by Gdf9-Cre or starting from growing oocytes as mediated by Zp3-Cre.
For more information on Philipp KALDIS's lab, please click here.