Newborn neurons undergo extensive morphological changes as they polarise to extend axons. In the developing spinal cord, newborn neurons extend axons towards their targets in response to cues from the surrounding tissues. This process is of fundamental importance as it ultimately leads to the formation of functional neural circuitry. Furthermore axon extension defects lead to a range of neurodevelopmental disorders.
Our work has shown that cells undergoing neuronal differentiation in the embryonic spinal cord delaminate from the neuroepithelium, resulting in shedding of the key signal transduction organelle, the primary cilium. Primary cilium shedding mediates acute cessation of Gli transcription mediated Shh signalling and facilitates cell cycle exit (Das and Storey, Science 2014, Kasioulis et al., eLife 2017). Following this, newborn neurons rapidly reassemble a new, molecularly distinct, primary cilium that now mediates Shh transduction through a Gli transcription independent mechanism to direct axon extension in the correct orientation (Toro-Tapia and Das, Science Advances 2020). However, the mechanisms through which this molecular remodelling of the primary cilium mediate the switch in interpretation of Shh interpretation remain unknown. To investigate this, the successful candidate will utilise cutting-edge live tissue and super-resolution imaging imaging of chick and zebrafish embryos to visualise and manipulate the dynamics of key ciliary Shh transducers and monitor the effects of these manipulations on neuron polarisation and axon extension. This approach will be combined with powerful proteomics-based approaches to identify novel molecular interactors that influence Shh signal interpretation.
Overall, this project will deliver physiologically relevant insights into the mechanisms through which the molecular plasticity of the primary cilium can be exploited by differentiating cells to actively reinterpret signalling cues and trigger key transitions in cell state and behaviour.
Entry Requirements
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience are particularly encouraged to apply.
How To Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.
For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/”
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