About the Project
Background
Neuronal differentiation is a fundamentally important developmental process that ultimately results in the 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. Cells undergoing neuronal differentiation in the embryonic spinal cord must exit the neuroepithelium to travel to the correct location in the developing body, a process that involves an acute loss of polarity. This is 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.
Details of the project
This project builds on our recent discovery of a new form of cell sub-division (apical abscission) that regulates shedding of the apical tips of newborn neurons, leading to an acute loss of cell polarity and retention of the centrosome (Das and Storey, Science, 2014). How these neurons re-establish their polarity and subsequently extend an axon in the correct orientation is now a key question in the field. This project will focus on the role of the retained centrosome in re-establishment of polarity in the new-born neuron using a highly interdisciplinary approach integrating pioneering cell and developmental biology techniques. The successful candidate will utilise cutting-edge live-tissue imaging techniques to visualise centrosomal dynamics and microtubule architecture rearrangements during neuronal differentiation in the embryonic spinal cord. This approach will be complemented by super-resolution microscopy to visualise the fine sub-cellular architecture of differentiating neurons.
Overall this project lies at the critical interface between cell and developmental biology and is therefore likely to provide physiologically relevant insights into the molecular mechanisms leading to neuron polarisation and axon extension.
Funding Notes
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships
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.
References
R. M. Das, K. G. Storey, Apical abscission alters cell polarity and dismantles the primary cilium during neurogenesis. Science 343, 200-204 (2014).
R. M. Das, A. C. Wilcock, J. R. Swedlow, K. G. Storey, High-resolution live imaging of cell behavior in the developing neuroepithelium. Journal of visualized experiments: JoVE, (2012).
R. M. Das, K. G. Storey, Mitotic spindle orientation can direct cell fate and bias Notch activity in chick neural tube. EMBO reports 13, 448-454 (2012).
Jones L, Villemant C, Starborg T, Salter A, Goddard G, Ruane P, Woodman P, Papalopulu N, Woolner S, Allan V, Dynein light intermediate chains maintain spindle bipolarity by functioning in centriole cohesion. J Cell Biol 207: 499-516
(2014)
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