Regulated development of the sensory nervous system results in the ability to feel pain and to sense body position. A major challenge has been to understand how neural crest precursor differentiation is controlled during development and how appropriate neurons are matched with target tissues in the periphery. This application focuses on the developmental regulation of the pain-sensing, calcitonin gene related peptide (CGRP)-containing sensory neurons in the dorsal root ganglion (DRG). CGRP-containing sensory neurons contact skin and gut peripheral target tissues and play pivotal roles in mediating pain sensation and local skin inflammation. This project is based on our novel observation that members of the transforming growth factor beta family -- including activins and bone morphogenetic proteins (BMPs) -- induce the pain sensing phenotype that includes CGRP expression in vitro. We hypothesize that specific TGFb family ligands from skin, blood vessel and gut target tissues induce the pain-sensing phenotype in sensory neurons during development. Studies in this application will test this hypothesis using both in vitro and in vivo functional assays. Noggin and follistatin will be used to identify classes of ligands that underlie CGRP induction by skin cell line factors. Native skin and gut will be assayed for biological activity and ligands in vitro, using assays developed with cell lines. The spatial and temporal localization of ligands and inhibitors will be carried out at critical periods of target contact to learn where and when bioactive factors are present. The role of TGFb family ligands in vivo will be tested by viral misexpression of ligand, inhibitor or BMP receptor. The long term objective of these studies is to understand the mechanisms that regulate neuronal differentiation. Even within the DRG, where relatively few neuronal types arise, little is known about what regulates how different types of neurons are generated from neural crest cells. The completion of the proposed studies will advance our understanding of the importance of target derived growth factors, and in particular the TGFb family ligands activin and bone morphogenetic proteins, in specifying sensory neuronal types from embryonic precursors.
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