Actin-dependent mechanisms of chromosome segregation in mammalian eggs
Every human life starts when an egg is fertilised by a sperm. Fertilisable eggs are produced from oocytes by a specialised form of cell division called meiosis (1). During oocyte meiosis, the chromosomes are segregated by a spindle machinery that is assembled from microtubules. For reasons we still do not fully understand, chromosome segregation errors in meiosis are remarkably high. As a result, mammalian eggs are frequently aneuploid – they contain the wrong number of chromosomes. Aneuploidy in eggs generally leads to embryo deaths and, when compatible with life, often results in genetic disorders such as Down’s syndrome. Our research is aimed at understanding the mechanisms that prevent aneuploidy in mammalian eggs for successful fertilisation and healthy embryogenesis.
For a long time, chromosome segregation was thought to rely entirely on microtubules, and the function of the actin cytoskeleton in this process has largely remained ignored. We have recently made a surprising discovery that an actin spindle that penetrates meiotic spindles is required for the accurate segregation of chromosomes in mammalian eggs (2). We showed that actin filaments that are incorporated inside meiotic spindles promote productive interactions between the chromosomes’ kinetochores and a stable population of microtubules (k-fibres) to drive accurate chromosome segregation in oocytes. Indeed, disruption of actin in oocytes leads to severe chromosome segregation defects and aneuploidy in eggs (2).
We now seek to dissect the mechanisms of how actin performs these critical functions in mammalian eggs using model systems including mouse and human oocytes. As a PhD student in the lab, you will apply established high-resolution and super-resolution live imaging assays, and quantitative image analysis to study actin dynamics in mammalian oocytes (2). You will in addition combine powerful loss-of-function techniques (3) with quantitative proteomics to understand how the actin and microtubule cytoskeletons co-operatively drive accurate chromosome segregation in oocytes. Ultimately, you will seek to gain mechanistic understanding of these functional cytoskeletal interactions outside the oocyte cytoplasm by reconstituting them in vitro from biochemically purified cellular components.
In the long-term, this fundamental research can be potentially exploited to prevent human embryo deaths and to improve the outcomes of assisted human reproduction.
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1. B. Mogessie, K. Scheffler, M. Schuh, Assembly and Positioning of the Oocyte Meiotic Spindle. Annu Rev Cell Dev Biol, (2018).
2. B. Mogessie, M. Schuh, Actin protects mammalian eggs against chromosome segregation errors. Science 357, (2017).
3. D. Clift et al., A Method for the Acute and Rapid Degradation of Endogenous Proteins. Cell 171, 1692-1706 e1618 (2017).