EXTRACELLULAR MATRIX AND AXONAL GUIDANCE IN C ELEGANS

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Cells migrate to new location during development of complex tissues. For example, during the development of the nervous system, pioneering axons migrate to specific target sites. How this type of navigation is accomplished has been a central issue in developmental neurobiology. Understanding this process could lead to new approaches to treat nerve tracts damaged by injuries and to new treatments for disorders which impair the ability of neurons to make correct synaptic connections. Several important developments now allow migrational guidance to be studied at the molecular level. UNC-6, a protein found in C. elegans, and netrins, the newly discovered vertebrate homologs of UNC-6, are the first molecules known to have a clearly defined role as guidance cues. These proteins are required for proper circumferential axon migrations in the developing nervous system of nematodes and vertebrates. They may have important functions in other migrations as well. Our goal is to understand how UNC- 6/netrin is able to guide axon and cell migrations. Our research will employ the powerful genetic and molecular techniques available in C. elegans to study development and function. Since members of the UNC-6 family are not only structurally conserved but appear to be remarkably conserved in function as well, our studies should have a broad impact on a growing field of study. UNC-6 is a laminin-related extracellular matrix protein which is required for dorsal and ventral migrations on the basal surface of the epidermis. As a simple hypothesis, UNC-6 is a secreted matrix guidance cue which is tracked by receptors expressed on the surface of migrating cells. One receptor (UNC-5) is known to be required for dorsal migrations. This model provides the basis to study structural arrangements and biological properties of the various components which comprise this guidance system. Major questions addressed in this proposal include: Which cells secrete UNC-6 and how is it distributed across the epithelium? What receptors (in addition to UNC-5) interact with UNC-6? What other extracellular matrix proteins interact with UNC-6? What are the nature of these interactions. The answers to these questions will provide the framework for understanding some of the most fundamental processes involved in forming the nervous system.