Extracellular Matrix and Axonal Guidance in C. elegans

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DESCRIPTION (provided by applicant): Nervous systems comprise a grid-like network of longitudinal and circumferential nerves. Several molecules have been found that guide circumferential migrations in C. elegans including UNC-6, the founding member of the netrin protein family. Little is known, however, about the molecular mechanisms that govern different responses individual migrating axons have to these guidance cues. These differences are important since they allow a variety of axon migration patterns to develop and a greater number of connections to form. Two approaches are proposed to study the molecular basis of the responses that axons have to guidance cues. First, genes are being identified and studied that affect the guidance of only subsets of circumferentially migrating axons. Specifically, these genes are required for migration patterns that are different from those of other circumferential axons. In one case, a gene has been found that is expressed in only a few neurons and which encodes a conserved cytoplasmic protein. This gene genetically interacts with genes encoding components of known axon guidance signaling pathways and is therefore a strong candidate for regulating neuron-specific axon guidance responses. Second, genetic screens are being used to isolate second site mutations that suppress the phenotypes of specific unc-6 mutations. These unc-6 mutations disrupt UNC-6 structural domains that are responsible for mediating distinct UNC-6 guidance activities. By isolating mutations that can suppress the phenotypes of these unc-6 mutations, proteins that interact with UNC-6 to help mediate the different UNC-6 activities might be identified. In a pilot screen, an extragenic mutation that reverts the uncoordinated movement and axon guidance defects caused by an unc-6 mutation has been recovered. Understanding the molecular mechanisms that control axon and cell guidance could prove critical for developing therapeutic agents that treat nerves damaged by injuries or disease.