Title: The mechanism and function of a contact-repulsive protein that regulates axon growth in the development of the nervous system
Background: The periodic outgrowth of vertebrate spinal nerves ensures that they are unimpeded by developing vertebrae, and is achieved by the subdivision of embryonic somites into anterior and posterior halves. Posterior cells repel growing axons, forcing them to traverse the anterior half-somites. We have identified a glycoprotein that has strong candidacy for this repellent. Being expressed selectively by posterior half-somite cells, it causes collapse of axon growth cones in vitro. Moreover in vivo knock-down by siRNA causes axons to traverse the posterior half-somites. We are now in the final stages of confirming the role of this contact-repellent and elucidating its molecular nature. It is also expressed on the astrocyte surface in the adult CNS, where it may regulate neuronal plasticity.
Aims: Using the growth cone collapse assay, the project will assess the mechanism of this repellent in spinal nerve development. We will test whether molecular inhibitors of its activity block collapse when applied to cultured neurons. We will also identify the cognate receptor on axon growth cones, and assess the expression and role of the repellent in development and the adult CNS.
Outcomes: Training in diverse molecular and cellular techniques will enable the student to make original observations, as the system is cutting new territory. Elucidation of this contact-repellent protein is expected to yield new molecular targets for therapeutic strategies to ameliorate neurodegeneration and promote regeneration.
- Protein synthesis dependence of growth cone collapse induced by different Nogo-A-domains. Manns, R., Schmandke, A., Schmandke, A., Jareonsettasin, P., Cook, G., Schwab, M.E., Holt, C. , Keynes, R. PLoS One (2014, in press)
- Differing Semaphorin 3A concentrations trigger distinct signaling mechanisms in growth cone collapse. Manns, R., Cook, G., Holt, C. & Keynes, R. Journal of Neuroscience 32, 8554-8559 (2012)