The developing nervous system comprises two distinct classes of cells, neuroglia and neuroblasts. Neuroglia direct early steps in the assembly of neural circuits, namely they support and guide migrating neuroblasts and pioneering axons. Differentiated neurons are the active elements of the completed circuits. The long-term objectives of this project are (1) to identify the molecular cues provided by neuroglia that guide axonal pathfinding, (2) to identify the receptors on growth cones that sense these cues, and (3) to understand how the activated receptors steer growth cones tracking these cues. In the genetic model C. elegans, a laminin-related matrix protein UNC-6 secreted by epidermal cells (glia) and a transmembrane receptor UNC-5 expressed by motor neurons work together to guide pioneering motor axons to their muscle targets. Using a combination of immunological and molecular genetic methods, the experimental plan addresses several specific questions: Does UNC-6 form a concentration gradient on the epidermis? Is laminin important for UNC-6 localization in the extracellular matrix? Does UNC-5 bind to UNC-6? If so, what signal is transduced to the cytoskeleton? What gene encodes the neuronal receptor for ventral migrations and is it structurally similar to the dorsal receptor UNC-5? Laminins and their receptors are phyletically ancient and highly conserved in structure. Laminins promote attachment, spreading, and locomotion of cultured cells and neurites, and may be required for epithelial polarization in vivo. Therefore, analysis of their roles in regulating cell migrations and attachments during normal and mutant development may aid the rational design of molecular therapies for invasive cancers. In addition, analysis of their roles in guiding pioneer axons may eventually allow the repopulation of axon tracts severed by injury or destroyed by disease.
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