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 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.

Reduction of nitric oxide level results in maturation promoting factor destabilization during spontaneous meiotic exit from diplotene arrest in rat cumulus oocytes complexes cultured in vitro

“…; Adhikari et al . ). Further, changes in the specific phosphorylation status of MPF and its cross talk with mitogen‐activated protein kinase (MAPK) have been reported during meiotic exit from metaphase‐II (M‐II) arrest in rat and mouse oocytes (Huo et al .…”

Genes Involved in the Processes of Cell Proliferation, Migration, Adhesion, and Tissue Development as New Potential Markers of Porcine Granulosa Cellular ProcessesIn Vitro: A Microarray Approach

“…CDK1-cyclin-dependent kinase, also known as CDC2, is a catalytic subunit of a protein kinase complex, also identified as the M-phase promoting factor, responsible for permitting mitosis to begin, and is similar among all eukaryotes. Adhikari et al (2016) proved that sustaining the prolonged meiotic arrest in female germ cells relies on the constant suppression of CDK1 activity, which is largely achieved by inhibitory phosphorylation of CDK1. This process is essential for safeguarding the integrity of the DNA in the growing oocytes, which has a positive effect on preserving the germ cell pool.…”

“…This process is essential for safeguarding the integrity of the DNA in the growing oocytes, which has a positive effect on preserving the germ cell pool. Disturbances in this processes cause the interruption of prophase I arrest, leading to a premature loss of female germ cells (Adhikari et al, 2016). Reis et al (2006) showed that, in fully grown mouse oocytes, the activity of CDK1 remains suppressed.…”

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

“…Four independently targeted ES cell clones were injected into C57BL/6 blastocysts to produce the chimeras. Mice with the Spdya loxP allele of C57BL/6J background were crossed with Zp3-Cre transgenic mice of C57BL/6J background (23,24) to delete exon 2 and generate Spdya +/− mice. Mice were housed under controlled environmental conditions with free access to water and food.…”