How do meiotic cells navigate the precarious transition between two M-Phases?

Keywords: Meiosis, kinase, signalling, ageing
Abstract: Sexual reproduction depends on the transmission of exactly one copy of each chromosome by the male and female gametes during fertilisation. Gametes become haploid during meiosis, which uniquely involves two rounds of chromosome segregation following a single round of DNA replication. The mechanisms by which this is accomplished are fundamental to our survival.
The mitotic cell cycle comprises alternating rounds of DNA replication during S phase and chromosome segregation during M-Phase. These events depend on the interplay between cell cycle kinases, phosphatases and ubiquitin ligases, acting as pacemakers to control the activities of chromatin-associated proteins. Accumulating evidence indicates that the meiotic divisions employ many elements of the mitotic machinery. A central aim of this project is to investigate how meiotic cells modify the cell cycle machinery to accomplish two successive rounds of chromosome segregation without an intervening S Phase. To tackle this question, we will combine expertise in structural biology with expertise in chromosome segregation in mouse and human oocytes. Mouse oocytes provide an ideal experimental system for investigating the Meiosis I (MI) to Meiosis II (MII) transition as they readily express fluorescently-tagged proteins, are amenable to high resolution live cell imaging, and enter a natural state of arrest at metaphase of Meiosis II.
Our work indicates that complete inactivation of CDK1-cyclinB1 is essential for chromosome segregation during MI in mouse oocytes. Moreover, live cell imaging during the MI-MII transition reveals that the condensation of chromosomes (typical of M Phase) precedes the accumulation of cyclinB1 during MII. These observations indicate that cell cycle regulators other than CDK1 act to orchestrate the MI-MII transition. In order to interrogate which catalytic and/or scaffolding functions of CDK-cyclin complexes underpin this behaviour, we will adopt a structurally-informed approach, exploiting our detailed understanding of the structures of CDK-cyclin complexes that control the mitotic cell cycle, alone and in combination with various regulators.
The specific aims of this project are (i) To apply insights from the structural biology of CDKs to further interrogate their proposed role in recruiting condensin to chromosomes during the transition from MI to MII, (ii) To determine the functional significance of rapid condensation of chromosomes following exit from MI and (iii) To investigate the mechanisms by which CDKs might mediate recruitment of condensin during the MI to MII transition. The findings of the project will shed new light on how the cell cycle machinery is modified to generate haploid gametes from diploid progenitors.