Mechanisms of axon guidance during development

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

In the past year, we have published three experimental papers and a review article that establish a novel model for the mechanism of axon growth and guidance. Over the past several years, we have used computational simulations of actin dynamics to dissect the modulation of growth cone actin organization that we had previously quantified experimentally in a growing axon in vivo. These simulations uncovered unexpected biophysical mechanisms that control the distribution of the actomyosin cytoskeleton in a growing axon (published in two papers last fall, and summarized in a review published this spring). As a test of these hypotheses, we then performed a series of experiments challenging an unexpected and perhaps counter-intuitive prediction of the computational model. As published in an additional paper last spring, genetic manipulations and imaging performed in vivo confirmed the computational predictions, strongly supporting the underlying hypothesis. We can therefore say with great confidence that the detailed molecular model we have proposed for how nerves grow, and how they know where to grow, indeed captures the essence of what goes on in a real nerve as it finds its way through the developing animal. In parallel with this project, we performed two collaborative projects that advance our understanding of how the molecular machinery of cytoskeletal reorganization is regulated by a specific cell surface signaling receptor. We found that the receptor, Notch, controls neuronal morphogenesis by regulating Abl kinase in two different, non-axonal contexts in the fly, rotation of photoreceptor neurons during eye development and regulation of dendritic branching. These observations demonstrate that the morphogenetic interaction of Notch with Abl that we have investigated in axons has more general application in multiple processes of neuronal cell biology.