Mechanisms of axon guidance during development

National Institute Of Neurological Disorders And Stroke

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Abstract

In the past year, we have made two significant intellectual advances in our analysis of axon growth and guidance. The central effort in this project is to understand how nerves grow, and why they may fail to grow. Previous work from the lab combined live imaging of single growing axons with genetic and biochemical analysis of genes and proteins that promote proper nerve growth during the development of the animal. The problem has been that the detailed mechanism of nerve growth involves processes that lie beyond the resolving power of any microscope. In the past year, therefore, we have turned to computational simulations of the motor machinery of the growing nerve, the actomyosin cytoskeleton, to try to connect our imaging with our genetics and biochemistry by generating testable predictions for how the biochemical machinery of the nerve generates the force to make the nerve grow, and processes the information that tells the nerve where to grow. This has been astonishingly successful; the pictures we generate computationally from biophysical first principles look extremely similar to the protein distributions we see in the microscope, and that similarity has been validated by rigorous quantitative analysis. 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. These computational papers are currently in preparation for publication. In parallel, we also turned our attention to the problem of why nerves fail to grow, or to be maintained, in disease. Here we found that the gene that is mutated in Huntingtons Disease, HTT, is a piece of the same nerve growth machinery we have been studying in early development. Indeed, HTT is a repressor of the Abl kinase that is the key regulator of actomyosin during nerve growth, and the defects that occur in an htt mutant are due to overactivity of Abl. Thus, the analysis we have done of initial nerve growth early in development turns out to explain the consequences of mutating a gene that causes neurodegeneration late in life.