Sensory neurons of the Dorsal Root Ganglia (DRG) are highly specialized cell types with diverse morphologies, patterns of connectivity, and functions. The long term objective of this proposal is to understand the molecular pathways that lead to such differences. Neurotrophins and their trk receptors are required for neuronal survival of distinct DRG sub-populations. Here, we propose that neurotrophins also play an instructive role during DRG neuronal development. This hypothesis predicts that the expression of a specific trk is sufficient to impose subtype specificity on these neurons. We will test this hypothesis by replacing one trk receptor with another in the mouse genome. In order to extend our knowledge of the molecular pathways beyond the neurotrophins, it is essential to find other genes involved in both developmental and functional aspects of DRG neurons. Because the neurotrophin/trk knockout animals lack specific DRG subtypes, we are analyzing these mice by gene-chip methods to identify genes uniquely expressed in distinct DRG classes. Our preliminary results have validated this strategy, and confirmatory in situ hybridizations indicate that the genes we have tested are specifically expressed in subtypes of DRGs. We will follow up on some of these molecules by (a) further characterizing their expression patterns during development; (b) finding interacting partners for those molecules involved in signaling using yeast two-hybrid analysis; and (c) testing their in vivo function using transgenic mouse experiments. As neurotrophins and trk receptors play key roles during development and in the pathology of childhood medulloblastomas and peripheral neuropathies, the further unraveling of molecular pathways controlling differentiation of DRG neurons will expand our understanding of neurodevelopmental defects and neuropathologies in humans.
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