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SoCoBio (Universities of Southampton, Kent, Sussex, Portsmouth and NIAB EMR)

A novel regulator of axon pathfinding in the brain: Regulation of axon-matrix interactions by the signalling protein alpha2-chimaerin

Primary Supervisor: Professor Sarah Guthrie (University of Sussex)

Secondary Supervisor: Dr Ben Goult (University of Kent)

Project Summary

Mutations in the protein alpha2-chimaerin (α2-chn) lead to the human eye movement disorder Duane Retraction Syndrome (DRS), a form of squint. This arises due to defects in axon guidance in the ocular motor system. We have shown that expression of mutant α2-chn causes defects akin to DRS in animal models, and compromise the ability of axons to extend and pathfind correctly.

Axon extension requires integrin-mediated adhesion complexes that engage with the underlying extracellular matrix (ECM). The periocular mesenchyme, through which ocular motor axons grow, contains abundant ECM proteins, and yet the role of α2-chn in regulating axon interactions with ECM is largely unexamined. Our hypothesis is that α2-chn regulates axon extension via regulating the adhesions between axons and the ECM. This project will combine the expertise of the two supervisors in α2-chn and its role in axon guidance (Guthrie) and the role of talin and vinculin in regulating integrin-mediated adhesion (Goult).

This project will provide the PhD student with a cutting-edge multidisciplinary training in biophysics and biochemistry (Goult) combined with cellular assays and neuroscience (Guthrie) to test the hypothesis that α2-chn regulates axon extension via interplay betwee α2-chn and talin.

We will use:

1) cellular and cell-free assays to test the interactions between α2-chn, talin and other adhesion components.

2) mechanobiology and biochemistry to analyse how α2-chn regulates the mechanical transduction pathways in which talin is involved.

3) neuronal cultures to analyse the behaviour of fluorescently-labelled α2-chn isoforms and adhesion components colocalisation in neurons. Live imaging will be used to study protein trafficking and cell behaviour, including axon extension and motility, and axon retraction/extension.

Impact: Successful completion of this project will reveal how axon guidance is regulated via adhesion complexes to enable correct brain wiring, pinpointing the role of two key proteins, α2-chn and talin.