Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan

Deepak Adhikari, Kiran Busayavalasa, JingJing Zhang, Mengwen Hu, Sanjiv Risal, Mustafa Bilal Bayazit, Meenakshi Singh, M. Kasim Diril, Philipp Kaldis, Kui Liu

Research output: Contribution to journalArticleResearchpeer-review

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 Cdk1 T14AY15F 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.

Original languageEnglish
Pages (from-to)1212-1225
Number of pages14
JournalCell Research
Volume26
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016

Keywords

  • Cdk1 inhibitory phosphorylation
  • female fertility lifespan
  • immature oocyte
  • meiotic prophase I

Cite this

Adhikari, Deepak ; Busayavalasa, Kiran ; Zhang, JingJing ; Hu, Mengwen ; Risal, Sanjiv ; Bayazit, Mustafa Bilal ; Singh, Meenakshi ; Diril, M. Kasim ; Kaldis, Philipp ; Liu, Kui. / Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan. In: Cell Research. 2016 ; Vol. 26, No. 11. pp. 1212-1225.
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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 Cdk1 T14AY15F 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.",
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Adhikari, D, Busayavalasa, K, Zhang, J, Hu, M, Risal, S, Bayazit, MB, Singh, M, Diril, MK, Kaldis, P & Liu, K 2016, 'Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan' Cell Research, vol. 26, no. 11, pp. 1212-1225. https://doi.org/10.1038/cr.2016.119

Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan. / Adhikari, Deepak; Busayavalasa, Kiran; Zhang, JingJing; Hu, Mengwen; Risal, Sanjiv; Bayazit, Mustafa Bilal; Singh, Meenakshi; Diril, M. Kasim; Kaldis, Philipp; Liu, Kui.

In: Cell Research, Vol. 26, No. 11, 01.11.2016, p. 1212-1225.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Risal, Sanjiv

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AU - Liu, Kui

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