Our Research

How to build the chromosome segregation machinery

How are genes passed on from cell to cell and from parents to children?
Genes must be passed on accurately from cell to cell and from parents to children. Failure to do so can be a cause or contributing factor in human illnesses, such as cancer or reproductive/birth defects. During eukaryotic cell divisions, cells dramatically change their organisation. DNA carrying genes are packaged into chromosomes and the spindle made of microtubules is assembled to segregate the chromosomes. Our lab aims to understand how chromosomes and the spindle are built and how they interact with each other at a molecular level using a genetics-led multidisciplinary approach in Drosophila.

How is the chromosome segregation machinery specialised in oocytes?
One of our recent research focuses has been dissection of molecular pathways which build the segregation machinery of meiotic chromosomes in oocytes. Mis-segregation in human oocytes is very frequent and indeed 20% of oocytes are estimated to mis-segregate chromosomes. This is a major cause of infertility, miscarriages and birth defects such as Down syndrome. The chromosome segregation machinery in oocytes shares similarities to that in mitosis, but also has crucial differences. These differences could be a source of high error rates in oocytes, but little is known about the molecular pathways that set up the chromosome segregation machinery specialised to oocytes. Defining these molecular pathways is crucial to understand error-prone chromosome segregation in human oocytes. Furthermore, evidence indicates that apparent oocyte-specific pathways also operate in mitosis, although less prominently, to ensure the accuracy of chromosome segregation. Therefore uncovering the molecular basis of these pathways is also important to understand how somatic cells avoid chromosome instability, a contributing factor for cancer development. Due to experimental challenges in mammalian oocytes, we take advantage of Drosophila oocytes as a "discovery platform". Their similarity to mammalian oocytes and suitability to a genetics-led mechanistic analysis make them an excellent model system.

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How are microtubules regulated for spindle assembly and function?
Mature oocytes lack centrosomes in many animal species, including humans and Drosophila. We hypothesise spindle assembly and function in oocytes should rely more on precise microtubule regulation than in mitosis, even though oocyte division and mitosis share similar regulatory mechanisms. We are still far from understanding the full identity and function of microtubule regulators. Even less is known about how these microtubule regulators themselves are regulated. By using genetics and 'omics approaches, we have identified microtubule regulators with functions and regulation pathways in oocytes that are distinct from mitosis. We are aiming to uncover how oocytes regulate microtubules to compensate for the absence of centrosomes. Furthermore, implication of our studies on microtubule regulation is well beyond cell division, as microtubules are universal features in eukaryotic cells and involved also in various processes including cell polarity, cell migration and intracellular transport.

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How do chromosomes adopt special organisation in oocytes?
In Drosophila oocytes, meiotic chromosomes cluster together to form a compact body, called the karyosome within the intact nucleus. A similar clustering of meiotic chromosomes has also been found in mouse and human oocytes. In wild-type mouse oocytes, this clustering is known to be correlated with developmental competency after fertilisation. Based on our studies, we proposed that the karyosome is crucial for the formation of one unified acentrosomal spindle. Surprisingly few mechanistic studies on the karyosome have ever been carried out. We have shown that breaking links between chromatin and the nuclear envelope is essential for karyosome formation. We are aiming to uncover the regulatory network which governs the formation of the karyosome in oocytes.

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