I am part of a team in the Clarke lab who are investigating the mechanisms by which neural progenitor epithelial cells establish apicobasal polarity within the developing neural rod of the zebrafish hindbrain. This is necessary for a smooth apical surface to form along the middle of the neural rod, from which the ventricle (lumen) then opens. The generation of epithelial tubes is a common requirement in many embryonic organs and the lumen position and proper apicobasal polarisation of surrounding cells is crucial to their function. Defects in epithelial cell polarity are at the route of many diseases, such as polycystic kidney disease (PKD), cystic fibrosis and cancer, to name a few. Therefore, understanding the fundamental principles of epithelial cell polarization is key, not only to further our understanding of normal development but also to determine what goes wrong in these diseases.
Using in vivo time-lapse confocal imaging, we have recently uncovered a novel mechanism of cell polarisation during lumen formation. We found that neural progenitor cells locate their centrosomes at and assemble a mirror-symmetric microtubule cytoskeleton around whichever point that they intersect the middle of the developing neural rod. This is necessary for the apically directed trafficking of proteins required for normal lumen formation, such as partitioning defective 3 (Pard3) and Rab11a to this point. To our knowledge, this is the first example of the initiation of apical polarisation part way along the length of a cell, rather than at a cell extremity. We propose a polarisation feedback loop by which initial Pard3 puncta might specify centrosomal location and then the centrosome organises the microtubule cytoskeleton around the tissue midline, which is necessary to reinforce Pard3 delivery to this point. I am currently investigating whether the centrosome is the chicken or the egg in this feedback loop.
I completed my PhD in 2009 with Robin Franklin at Cambridge University in collaboration with a biotechnology company Summit plc. (formerly DanioLabs Ltd.). We characterised the time-course of developmental myelination in zebrafish and designed medium throughput in vivo screens with the aim of identifying compounds that could be used to combat myelin disorders such as multiple sclerosis. This work resulted in the identification of 25 targets that are able to alter oligodendrocyte lineage cell recruitment or proliferation and/or mbp transcript levels in vivo.