(MRC DTP) Cytoskeletal re-arrangements leading to correct neuron polarisation during vertebrate CNS development

Neuronal differentiation during embryonic development is a fundamentally important process that ultimately results in the formation of functional neural circuitry. We have recently discovered a novel cell-biological process that mediates acute loss of cell polarity, dismantling of the primary cilium and retention of the centrosome by newborn neurons as they delaminate from the neuroepithelium (apical abscission) (Das and Storey, Science, 2014). This loss of polarity results in a potentially hazardous cell state, requiring tight control, as the nascent neuron must now rapidly re-establish its polarity. This repolarisation is crucial, as it determines the position of axon outgrowth, an important step in establishment of normal tissue architecture and formation of functional neural circuitry. Errors in this critical process lead to several neurodevelopmental disorders and have also recently been identified as one of the earliest indicators of dementias such as Alzheimer’s and Huntington’s disease.

How newborn neurons re-establish their polarity and subsequently extend an axon in the correct orientation is now a key question in the field. To understand the molecular and cell-biological mechanisms that direct this in the physiologically relevant context of spinal cord development, the lab utilises state-of-the-art live-tissue imaging and super-resolution imaging techniques (Das and Storey, EMBO Reports, 2012, Das and Storey, Science, 2014, Kasioulis et. al., eLife, 2017). These cutting-edge techniques are unique to the lab and facilitate imaging of cell behaviour at previously unprecedented temporal and spatial resolution.

The centrosome is the major microtubule organising centre (MTOC) in most cell types, and so plays an important role in directing morphological transformations. The role of the centrosome during neuron repolarisation is unknown and its role during axonogenesis is controversial. Previous studies investigating this have relied on cultured cells, and so fail to recapitulate cell behaviour in the context of a developing tissue. This project will utilise long-term high resolution live-tissue imaging and advanced super-resolution imaging to determine the normal dynamics of the centrosome and its role as a MTOC during neuron repolarisation and axonogenesis. The MTOC function of the centrosome will then be impaired at different stages of neuron repolarisation and axonogenesis and the effect of this on axon extension monitored. Finally, the molecular mechanisms regulating microtubule nucleation at different stages of neuronal differentiation will be dissected. Overall, this study will establish the molecular and cellular mechanisms driving neuron polarisation and axonogenesis.

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject