Every time a human egg cell divides, its chromosomes can end up in the wrong place—a major cause of infertility, miscarriage, and conditions like Down syndrome. The problem lies in how the egg builds its spindle, the microscopic scaffold that pulls chromosomes apart, without the usual cellular assembly instructions and inside a cell that is far larger than a typical body cell. Researchers know how this works in ordinary cells, but the egg’s unusual size and lack of centrosomes—the normal microtubule-organising hubs—make it a molecular blind spot. This project uses fruit fly eggs as a discovery platform to answer three fundamental questions: how chromosomes kick-start spindle assembly in that vast volume, what the spindle’s surrounding envelope does, and how proteins cooperate to build a stable bipolar structure. The work is fundamental science with no immediate clinical application. But because the same mis-segregation errors plague human eggs, understanding the molecular mechanics in flies could eventually point toward why human eggs so often get it wrong—and how that might be corrected.
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Chromosome mis-segregation is frequent in human meiotic oocytes and a major cause of infertility, miscarriage and congenital conditions, such as Down syndrome. Chromosome segregation is mediated by a spindle made of bipolar microtubule arrays. Spindle assembly in oocyte meiosis is challenging, as it is done in the exceptionally large oocyte volume and without centrosomes, the main microtubule-organising centres in mitosis. Despite the potential medical significance, spindle assembly in oocytes is less well understood at the molecular level than in mitosis, due to technical difficulties. To overcome these difficulties, we use Drosophila oocytes as a "discovery platform" that can uniquely combine genetic, cytological and biochemical approaches. The key goal of this proposal is to address the following fundamental unanswered questions at the molecular level, based on our new innovative methods and unpublished findings. 1.How do chromosomes locally activate spindle assembly in the large oocyte? 2.What is the role of spindle envelope/matrix which embeds the spindle in oocytes? 3.How do proteins co-operatively assemble the stable bipolar spindle in oocytes? Answering these long-standing questions will reveal how the bipolar stable spindle is assembled without centrosomes in the large oocytes. It could potentially provide unique insights into frequent chromosome mis-segregation in human oocytes.
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