The kinase Mps1 is required to generate oocytes with the correct chromosome count for fertilisation

In a recent study1 published in Nature Communications, Katja Wassmann's team2 at the Institut de Biologie Paris-Seine (IBPS) tries to elucidate the molecular mechanisms underlying chromosome segregation in mammalian oocytes, to gain a better understanding of what goes wrong so frequently in human oocytes.

In humans, more than 20 % of oocytes are aneuploid, meaning that they harbour the wrong number of chromosomes. When fertilized, these oocytes will give rise to aneuploid embryos. Most aneuploidies in humans are not viable, and lead to spontanous abortion within the first trimester of pregnancy. Only some trisomies (the most prominent being Trisomy 21) survive up to birth. 

Female and male gametes fuse to create the first cell of the future embryo, the zygote. Eukaryotic organisms harbour two copies of the genome, they are diploid. To avoid duplicating the genome, the cells giving rise to gametes have to undergo two specialised cell divisions named meiosis I and II, to reduce their genome into half. Hence, oocytes and spermatozytes contain only one copy of the genome, they are haploid. To achieve the haploid state, germ cells first separate chromosome pairs in meiosis I, and sister chromatid pairs in meiosis II. Each chromosome consists of two sister chromatids, and to avoid separating sister chromatids in meiosis I already, the "glue" holding sisters together is removed in a step wise manner during the meiotic divisions: from chromosome arms in meiosis I, and from a specific site named the centromere, in meiosis II.

This molecular "glue" holding sister chromatids together is named Cohesin. Cohesin is removed by cleavage of one of its subunits.Cleavage of Cohesin at the centromere in meiosis I is prevented by a protein named Shugoshin ("Guardian Spirit" in Japanese)- centromeric Cohesin is therefore "protected" from cleavage in meiosis I. The study now published by the group MOM shows that Shugoshin is recruited to the centromere in a manner depending on the kinase Mps1. The team furthermore demonstrated that at least two distinct pools of Shugoshin exist at the centromere region in oocyte meiosis I- one pool, localized by Mps1 kinase to bring about protection of centromeric cohesin, and another one depending on the kinase Bub1 and phosphorylation of the Histone mark H2AT120, which fulfills an alternative function. Loss of the protective pool of Shugoshin at the centromere results in untimely removal of Cohesin at the centromere in meiosis I, precocious segregation of sister chromatids, and the generation of aneuploid oocytes.

Aneuploidy rates of human oocytes increase dramatically with the age of the mother. The results of this study may help us gain insights into what goes wrong with age also in human oocytes. It will be important to address whether kinase activity of Mps1 decreases with the age of the mother, and whether this leads concomitantly to increased precocious separation of sister chromatids in meiosis I.

The results of this study have been published on the INSB website and in the CNRS newsletter, En direct des labos.

1. Mps1 kinase-dependent Sgo2 centromere localisation mediates cohesin protection in mouse oocyte meiosis I, Nature Communications, 2017.

2. Team MOM - Mammalian Oocyte Meiosis, UMR 7622, Laboratoire de Biologie du Développement, IBPS.

Caption: The image shows an oocyte in meiosis I, just before chromosome segregation. Paired chromosomes (in blue) attached to the bipolar spindle (in green) with their kinetochores (in red) are shown. Overlays of the original acquisitions with the confocal microscope have been treated with Arivis 4D for 3D rendering.