Nervous system function is absolutely dependent on the complex pattern of synaptic connectivity formed during development, and maintained during neuronal regeneration. The distal tip of the extending neurite, the growth cone, is in large part responsible for distinguishing between myriad pathways and targets. The growth cone membrane contains very high levels of the GTP-binding protein, G-o This concentration suggests that G-o participates in a signal amplification system allowing a single filopodial contact with a shallow gradient of attractant or repulsive factors to dramatically alter growth cone motility. To test this hypothesis, mutated alpha subunits of G proteins which are constituitively activated or inactivated will be expressed in various neuronal cells and the effect on neurite outgrowth will be evaluated. Intraneuronal proteins which determine a cell's intrinsic growth potential might function via G-o. The protein GAP-43 may be one such molecule, since it is highly induced during neuronal development and regeneration, and is localized to the growth cone membrane. GAP-43 can activate purified G-o and this project will examine whether, within cells, GAP-43 modulates second messenger systems by activating G proteins. The two second messenger systems to be examined are the adenylate cyclase system of epithelial cells, and the phosphoinositide-mediated chloride channel response of the X. laevis oocyte. There are many extracellular molecules which alter growth cone motility. One group of membrane-bound factors acts extracellularly to collapse growth cones at synaptic targets, and preliminary evidence indicates that their mechanism of action may also involve G-o. G protein-coupled receptors for such molecules will be searched for in an expression cloning system. Thus, a focus on G protein transduction in the growth cone may explain the action of known regulators of growth cone function, and allow identification of novel proteins in the growth cone. Such a detailed molecular analysis of the growth cone should have broad clinical applications. Failure of these mechanisms might underlie unexplained developmental disorders of the nervous system. By pharmacologically enhancing the normal function of such pathways, repair of the adult nervous system after multiple types of injury might be increased. It is also probable that the same system contributes to synaptic plasticity in the adult nervous system, and a failure of this system might therefore account for some unexplained degenerative disorders of the nervous system.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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Yale University
Schools of Medicine
New Haven
United States
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