Signal transduction is precisely controlled within intracellular compartments, and a major mechanism for achieving this is by using vesicles to transport signaling complexes. This concept is highly relevant to neurotrophic action, and to mechanisms of axon outgrowth in the developing nervous system and in response to nerve injury. Vesicle-mediated pathways also represent potential therapeutic targets for Alzheimer's Disease, psychotic disorders, and nerve injury. Synapsins, a family of abundant, neuron-specific phosphoproteins that coat vesicles, are ideal candidate molecules for regulating signal transduction on vesicles. In addition to binding vesicles, synapsins bind to signaling molecules that affect neurotrophic signaling, such as the adapter Grb2, PI3 kinase, and an essential co-factor for neurotrophic signaling, 14-3-3z. Synapsins bind to 14-3-3z at a site which acts as a phosphorylation-dependent molecular switch to regulate the growth of spinal axons in response to cAMP in Xenopus embryos. The central hypothesis is that synapsins are an integral part of a larger signaling complex located on vesicles. We hypothesize that synapsins, through interactions with 14-3-3z and other signaling molecules, regulates signaling cascades while situated on vesicles. We will test our central hypothesis by: 1) Identifying the signaling pathways modulated by synapsins and 14-3-3z; 2) Establishing the role of 14-3-3z phosphorylation in neuronal development; 3) Determining the spatial relationships between synapsins, 14-3-3z, and other cAMP/neurotrophic signaling molecules on vesicles. The results will contribute not only to a better understanding of the molecular basis of neural development, but could also provide insights into the pharmacological treatment of neuropsychiatric diseases.
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