Neuronal cell body and growth cone migrations shape the overall pattern and connectivity of nervous systems. The objective of the proposed research is to investigate the mechanisms that control neuronal migrations. Understanding these basic mechanisms could lead to insights into how damaged nervous systems might be repaired. The application has four specific aims. To determine whether EGL-20 Wnt acts as a guidance cue for the HSN. The migrations of the HSN motor neuron require the Wnt homolog EGL-20, and preliminary experiments suggest that EGL-20 acts as a guidance cue, a novel activity for a Wnt. To determine whether EGL-20 guides the HSNs to their destinations, EGL-20 will be misexpressed. Downstream components in EGL-20 Wnt will be identified to determine whether they act in the HSN. 1. To determine how the CAM-1 Ror kinase antagonizes EGL-20 in HSN migration. Genetic interactions between the egl-20 and cam-1 mutations indicate that these genes antagonize each other in HSN migration. CAM-1 could alter the distribution of EGL-20 by directly binding to EGL-20. Alternatively, CAM-1 could encode a component of a separate signaling pathway that antagonizes EGL-20. A series of genetic and molecular experiments are proposed to distinguish between these hypotheses. 2. To further characterize the role of Abelson oncogene ABL-1 in cell migration and identify genes that act in the ABL-1 pathway. The Abelson oncogene plays a central role in the growth cone migrations of other organisms. In C. elegans, ABL-1, like CAM-1, antagonizes the activity of EGL-20 in HSN migration. Experiments are proposed to determine which portions of ABL-1 function in migration, to determine where ABL-1 functions, and to identify molecules that act with ABL-1. 3. To define the roles of VAB-8/UNC-51 interactions in cell and growth cone migrations. VAB-8 interacts physically with the conserved serine/threonine kinase UNC-51. Preliminary experiments also suggest that UNC-51 can phosphorylate VAB-8L. The functional significance of the VAB-8/UNC-51 interactions and the role of VAB-8 phosphorylation will be tested.
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