MOM : La Méiose dans l'Ovocyte de Mammifères

Haploid gametes, named oocytes and spermatozoa, are generated through two specialized cell divisions without intervening S-phase, from a diploid precursor cell. Missegregation of chromosomes in meiosis has severe consequences, because it leads to the generation of aneuploid gametes (harboring the wrong number of chromosomes)

In humans, meiosis in oocytes is error prone, with an estimated 20 % of fertilizable oocytes being aneuploid. Most trisomies, such as trisomy 21, are due to chromosome missegregations in female meiosis. Furthermore, oocytes of women close to menopause show a dramatic age-dependent increase in meiotic missegregations. The general aim of our research projects is to gain a better understanding of cell cycle regulation and checkpoints in female meiosis. The model systems we are using are mouse oocytes for imaging approaches, and alternative model systems such as ascidian oocytes for biochemistry.

Aneuploidy is a hallmark of cancer cells. Our research also aims at elucidating the mechanisms that control correct chromosome segregation in mitosis such as the spindle assembly checkpoint.

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The general aim of our research projects is to gain a better understanding of cell cycle regulation in meiosis. We aim at elucidating the mechanisms of chromosome segregation during female meiosis to understand why it goes wrong so frequently. Chromosomes are held together through a protein complex named Cohesin, which has to be removed in a two-step manner during the two meiotic divisions. We study how the centromere associated pool of Cohesin is removed only in meiosis II. Chromosome segregation in meiosis also requires a specific orientation of chromosomes in meiosis I, and sister chromatids in meiosis II. The second aim of our projects is to elucidate how the so-named spindle assembly checkpoint, which prevents precocious Cohesin removal, recognizes and promotes correct attachments in meiosis. The model system we are mainly using are mouse oocytes, but we also use complementary systems such as Xenopus laevis or ascidian oocytes for biochemical aproaches, when required.

  • 1) Deprotection of Centromeric Cohesin in Meiosis II

Chromatid pairs are segregated in meiosis I, and single chromatids in meiosis II. To maintain chromatid pairs together throughout meiosis I, centromeric Cohesin has to be protected from proteolytic cleavage by Separase through Shugoshin 2 (Sgo)- dependent recruitment of PP2A. PP2A is a phosphatase that dephosphorylates a meiosis-specific subunit of the Cohesin complex and thereby prevents Cohesin removal by Separase. PP2A and Sgo2 are localised to the centromeres in meiosis I , but strikingly, they also co-localize in meiosis II. Therefore, localisation of Sgo2 and PP2A alone cannot explain why centromeric Cohesin is protected in meiosis I, and why this protection is lost in meiosis II ("deprotected"). We have recently identified I2PP2A and Cyclin A2 as being essential for deprotection of centromeric Cohesin in oocytes by counteracting PP2A. Our current projects aim at identifying the signaling pathways required for deprotection in female meiosis II.

  • 2) Spindle Assembly Checkpoint Control in Meiosis

Chromosome segregation in mitosis and meiosis depends on the activity of the APC/C (anaphase promoting complex/cyclosome), an E3 ubiquitin ligase that targets key cell cycle regulators for degradation. Degradation of Cyclin B and Securin is required for full activation of the protease Separase. Separase cleaves one subunit of the Cohesin complex (Scc1 in mitosis, Rec8 in meiosis) to allow the separation of paired sister chromatids in mitosis, and paired chromosomes in meiosis I. Activation of Separase depends on the inactivation of the Spindle Assembly Checkpoint or SAC. The SAC verifies that correct tension-generating attachments to the bipolar spindle are present on kinetochores. In the presence of erroneous attachments, metaphase to anaphase transition is prevented through the inhibition of the APC/C.  

Chromosome attachment in meiosis I is fundamentally different from mitosis: two sister chromatids are oriented side-by-side towards the same pole (monopolar attachment), and not towards opposite poles (bipolar attachment). Nevertheless, we and others have been able to show that the SAC is active in meiosis I and components of the mitotic SAC are essential for generating fertilizable oocytes of the correct ploidy. Our projects aim at elucidating the role of certain SAC components for mono-orientation of sister chromatids in mouse meiosis I, and at clarifying the molecular link between error correction and SAC control. More generally, we want to understand how wrongly attached kinetochores are recognized in meiosis I and II.