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Click here to search FindAPhD.com for PhD studentship opportunities(BBSRC DTP) Primary cilium mediated interpretation of signalling during neuronal differentiation in the developing vertebrate embryo
About the Project
We invite applications for a fully funded PhD position to work on an exciting project investigating the mechanisms through which differentiating neurons of the vertebrate embryo dynamically interpret extracellular signals to achieve normal axon extension. This question is of critical importance as errors in axon extension are associated with a vast range of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, and a range of brain malformations. Our work therefore aims to ultimately inform future therapeutic interventions to alleviate or prevent these conditions.
To understand the cellular mechanisms that direct neuronal differentiation in the physiologically relevant context of vertebrate embryonic development, we deploy state-of-the-art timelapse imaging and advanced super-resolution imaging techniques in combination with the latest optogenetic methods to record and manipulate cellular behaviour and function. Our work has demonstrated that neuronal differentiation is punctuated by distinct intermediate cell states. These cell state transitions are regulated through molecular remodelling of the key cellular signal transduction organelle, the primary cilium, which allows differentiating neurons to dynamically re-interpret Sonic Hedgehog (Shh) signalling as they progress through differentiation (1-3).
In addition to Shh signalling, differentiating neurons must also correctly interpret and integrate several other signalling cues, including BMP signalling. Correct interpretation of BMP signalling is first required for initiation of neuronal differentiation and then for axon extension in the correct orientation (4). Furthermore, BMP signalling has recently been shown to also be transduced through the primary cilium (5). However, the mechanisms through which BMP signalling is transduced and actively interpreted by the primary cilium of differentiating neurons to ultimately achieve correct axon extension remain unknown.
This project will investigate:
- The precise temporal dynamics of the changes in BMP interpretation during neuronal differentiation.
- The mechanisms through which molecular remodelling of the primary cilium facilitates dynamic interpretation of BMP signalling
- The molecular mechanisms through which dynamic interpretation of BMP signalling facilitates neuronal differentiation and axon extension.
The successful candidate will join a dynamic and forward-thinking research group with a strong focus on achieving scientific excellence by working together as a team. The candidate will also join a cohort of students in a comprehensive training programme, including student-led symposia and scientific retreats. They will have the opportunity to attend national and international conferences and symposia to present their findings and will benefit from in-depth advice on career progression from the supervisory team.
Relevant links
https://research.manchester.ac.uk/en/persons/raman.das
https://research.manchester.ac.uk/en/persons/shane.herbert
Eligibility
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/bbsrc-dtp/
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]
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/
Funding Notes
References
2. I. Kasioulis, R. M. Das*, K.G. Storey*, Inter-dependent apical microtubule and actin dynamics orchestrate centrosome retention and neuronal delamination. eLife 6:e26215, (2017).
*Co-corresponding authors
3. R. M. Das, K. G. Storey, Apical abscission alters cell polarity and dismantles the primary cilium during neurogenesis. Science 343, 200-204 (2014).
4. A. M. Bond, et al., The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation. Dev Neurobiol 72(7): 1068-1084 (2012).
5. M. Mönnich, et al., CEP128 Localizes to the Subdistal Appendages of the Mother Centriole and Regulates TGF-β/BMP Signaling at the Primary Cilium. Cell Reports 22(10): 2584-2592 (2018).
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