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.