The RAF/MEK/ERK signaling cascade is a key mediator of neurotrophin signaling via Trks and is among the most studied signaling cascades in all of biological sciences. In the nervous system, RAF/MEK/ERK signaling is thought to regulate morphological development, differentiation, and neuronal plasticity in response to extracellular signals. Despite its presumed importance, the role of RAF/MEK/ERK signaling in nervous system development and function in vivo is largely unknown due to the fact that the initial round of gene targeted animals has not been informative. We propose a conditional mutagenesis approach to testing the roles of RAF/MEK/ERK signaling on axon growth, differentiation, and regeneration using dorsal root ganglion (DRG) neurons as a model system. Specifically, we propose to test the following five hypotheses: /. RAF kinase signaling regulates morphological development but not survival of DRG neurons. II. RAF kinase signaling regulates differentiation of DRG neurons. III. RAF kinase signaling is required for efficient axon regeneration after peripheral axotomy. IV. Conditional elimination of MEKs will yield phenotypes discordant from those produced by conditional elimination of RAFs V Conditional elimination of ERKs will yield phenotypes discordant from those produced by elimination of RAFs and those produced by elimination of MEKs. Defining the biological roles of the RAF/MEK/ERK cascade using conditional gene targeting in mice will provide key insights into the regulation of axon growth, neuronal differentiation and regeneration. The results will also speak to the likely efficacy and potential toxicity of the many drugs being developed to inhibit functions of this cascade for the treatment of neural tumors and chronic pain states.
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