Connecting Ca2+ and cell migration to development and cancer

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Changes in the concentration of cytosolic Ca2+ drive a multitude of cellular events from those at the very start of life (fertilization), through development and ultimately to those culminating in cell death. These Ca2+ signals often initiate from intracellular Ca2+ stores which includes a variety of acidic organelles such as lysosomes referred to as "acidic Ca2+ stores". Defective signalling through acidic Ca2+ stores has been implicated in a number of disorders including Parkinson disease highlighting the need to understand organellar Ca2+ transport and the cellular processes that it regulates.The neural crest is a transient, migratory population of cells found in all vertebrate embryos that differentiate into a wide range of cell types, including neurons and glial cells of the peripheral nervous system and cartilaginous and skeletal elements in the head. Understanding the mechanisms driving migration is critically important to understand not only morphogenesis but also cancer metastasis - a process to which neural crest migration is often likened.This project builds on our very recent findings that have identified novel Ca2+ transporters on acidic Ca2+ stores and shown that they regulate migration of neural crest cells in vivo. The overall aim is to combine expertise in endo-lysosomal Ca2+ signalling (Patel) and cell migration (Mayor) to further test the hypothesis that acidic Ca2+ stores are required for cell motility. The student will use both chemical and molecular methods to manipulate Ca2+ signaling proteins and examine the effect on cytosolic Ca2+ and migration. This will be achieved using a range of molecular cell biology and imaging approaches, amphibian neural crest cells to study cell migration in vivo, and neuroblastoma, one of the most common childhood cancers, for in vitro analyses.The successful outcome of this project will provide urgently needed molecular insight in to the mechanisms of endo-lysosomal Ca2+ signalling and cell migration during (patho)physiologically relevant processes.