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Unravelling the role of Lrig2 during neuromuscular development


   Faculty of Biology, Medicine and Health

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Motor nerves connect the spinal cord and brain with muscles in our face, arms, legs and internal organs. The motor nerves send signals which tell these muscles to contract. When motor nerves go wrong, people experience unpleasant and crippling symptoms, often lasting many years. Curative treatments for such diseases are urgently needed but are currently almost nonexistent.

We know that diseases of motor nerves have varied causes, including diseases such as diabetes or genetic causes. At the University of Manchester, we discovered that mutation in the LRIG2 gene causes urofacial syndrome (UFS), a congenital disease causing grimacing of the face and defects in bladder voiding. Lrig2 mutations prevent normal peripheral nerve patterning and cause functional nerve defects. It is a transmembrane protein thought to regulate growth factor signalling, but very little is known about its biological role(s) in vivo. The goal of this project is to characterise the role of Lrig2 in motor nerve development to help us understand the pathobiology and aetiology of UFS.

We study the role of Lrig2 during the development of nerves in the frog Xenopus tropicalis. Xenopus has unique advantages: it is easy to obtain large number of eggs, which develop externally and are accessible at all stages of development. The genome of Xenopus tropicalis has been sequenced and shows striking similarities with the human genome, meaning that findings from Xenopus provide insight into many human conditions and diseases.

We have developed a frog knockout for lrig2 gene. Initial analyses of the phenotype show that Lrig2 is essential for spinal cord and somite formation. Using this model, we will answer fundamental questions regarding Lrig2 biology: What is its signalling activity? What is the role of Lrig2 during nerve and muscle development? What is its role during mammalian neurogenesis? In turn, these results will inform the logical design of novel therapies to help damaged nerves to grow normally in patients affected by diseases such as UFS.

The student will receive state-of-the-art training in working with an in vivo model (Xenopus tropicalis) using gene editing technology such as Crispr-Cas9 technology to generate gene knockouts and characterising their phenotypes (immunofluorescence, changes in gene expression). The student will also perform biochemical experiments (monitoring of the activity of signalling pathways in mutant vs wildtype) and learn common molecular biology techniques such as cloning, generation of synthetic mRNAs and analyses of gene expression by RT-qPCR.

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, particularly in cell culture and molecular biology, 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 PhD Genetics

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/”

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. For more information please visit http://www.internationalphd.manchester.ac.uk


Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website View Website

References

De Vincenti, A. P. et al. (2021) ‘Lrig1 and Lrig3 cooperate to control Ret receptor signaling, sensory axonal growth and epidermal innervation’, Development. The Company of Biologists, 148(16). doi: 10.1242/dev.197020.
van Erp, S. et al. (2015) ‘Lrig2 Negatively Regulates Ectodomain Shedding of Axon Guidance Receptors by ADAM Proteases.’, Developmental cell. Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.: Elsevier, 35(5), pp. 537–552.
Roberts, N. A. et al. (2014) ‘Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus’, Human Molecular Genetics. Centre for Genomic Medicine and Centre for Paediatrics and Child Health, Institute of Human Development, Faculty of Medical and Human Sciences.: Oxford University Press, 23(16), pp. 4302–4314. doi: 10.1093/hmg/ddu147.
Simion, C., Cedano-Prieto, M. E. and Sweeney, C. (2014) ‘The LRIG family: enigmatic regulators of growth factor receptor signaling.’, Endocr Relat Cancer. Department of Biochemistry and Molecular MedicineUniversity of California Davis School of Medicine, 4645 2nd Avenue, Sacramento, California 95817, USA., 21(6), pp. R431–R443.
Stuart, H. M. et al. (2013) ‘LRIG2 Mutations Cause Urofacial Syndrome’, The American Journal of Human Genetics. Cell Press, 92(2), pp. 259–264. doi: 10.1016/j.ajhg.2012.12.002.

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