MOM - Mammalian Oocyte Meiosis

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 this leads to the generation of aneuploid gametes (harboring the wrong number of chromosomes).

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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 Xenopus laevis 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. A third aim is to gain a better understanding of cell cycle regulation in oocyte meiosis, by studying oocyte-specific roles of A- and B-type cyclins. The model system we are mainly using are mouse oocytes, using genetically modified mouse strains and sophisticated imaging approaches on live and fixed oocytes. Additionally we use synchronized Xenopus laevis oocytes for biochemical approaches not feasible in the mouse.

  • 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 found that the kinase Mps1 is required for Sgo2 dependent protection f centromeric cohesin. Furthermore we have identified I2PP2A/Set and Cyclin A2 as being essential for deprotection of centromeric Cohesin in oocytes. Our current projects aim at identifying the signaling pathways required for protection and 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 oocytes of the correct ploidy. Our projects aim at elucidating the role of the SAC as oocytes progress from meiosis I into meiosis II. We address the role of SAC and the molecular link between error correction and SAC control in meiosis I and II.

  • 3) Cell Cycle Control in Oocyte Meiosis

In meiosis, two cell divisions without intervening S-phase take place. Using mouse and X. laevis oocytes we are interested in understanding how cell cycle progression is regulated during the two divisions in oocytes, and how Separase is inactivated between meiosis I and II. We use both mouse and frog oocytes to determine the role of A-and B-type cyclins for meiotic progression. Furthermore we study how the meiotic cohesin Rec8 is recognized and cleaved by Separase in mouse oocyte meiosis I and II.

Ongoing Collaborations