Mechanisms of axon guidance during development

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

We previously developed a computational model of actomyosin interactions in axons and found that it can account for many aspects of axon growth and turning. However, computational constraints limited the number of variables the model could incorporate. Improvements in hardware and software have now allowed us to make the model more realistic, particularly by making the myosin model more sophisticated (treating myosin heads as discrete elements and calculating separately the dynamics of different heads; also by accounting for the volume of the myosin molecule itself). These modifications improve the model, for example, by better representing the distribution of forces in the actomyosin network and avoiding non-physiological bending and bundling of actin filaments. So far, we find that these changes have not altered any of the fundamental interpretations we drew about mesoscopic distributions and dynamics of actin and myosin in the axonal growth cone, but provide new insights into their source, properties, and significance. Simulations are underway to test this interpretation further, and we expect to prepare a manuscript based on the new findings over the next three months. Our prior studies of Abl tyrosine kinase signaling and its regulation of actin have been based almost entirely on examination of specific axonal growth cones. In the past several years we have expanded that focus to test Notch-regulated Abl function in cell migration and dendritic morphogenesis. In the current year, we have also examined Abl function in synapse morphogenesis and homeostasis (in collaboration with the Serpe lab, NICHD). That collaboration has revealed a mechanism that is conserved from flies to mammals by which a specific cell surface signaling receptor complex (Semaphorin-Plexin-Neto/Neuropilin) robustly controls various homeostatic processes across phylogeny by both recruiting Abl kinase and amplifying the activity of that kinase through various allosteric interactions. This discovery has widespread physiological implications for synaptic homeostasis as well as other signaling processes including tumorigenesis. A paper presenting these data is currently in journal review.