Spinal muscular atrophy (SMA) is an autosomal disease caused by deletion or mutation(s) of thesurvival motor neuron 1 (SMN1) gene. A highly homologous gene, SMN2, is present in all patients but yields low levels of the full-length SMN protein. This low expression of the SMN protein results in selective death of spinal motor neurons and muscle paralysis. SMN is ubiquitously expressed and contributes to the assembly of ribonucleoprotein complexes, transcriptional regulation, neurite outgrowth, and cell survival. However, exactly why motor neurons selectively die in SMA remains unclear. Accumulated evidence indicates that SMN localizes into neuronal processes where it associates with proteins involved in RNA transport and translation. Reduced levels of SMN protein decrease axonal transport of b-actin mRNA, with a presumed decrease in localized b-actin translation and defects in neurite outgrowth. However, the effect of SMN reduction on localized translation of other mRNAs has not been tested and it is not clear if SMN plays a role in axonal mRNA localization, translation, or both. Furthermore, it is not clear whether decreases in axonal mRNA transport with SMN depletion are restricted to motor neurons or if other neuronal populations are affected. In this project we are directly testing both of these possibilities. The overall objective is to determine if SMN affects neurite outgrowth by controlling axonal mRNA transport and localization to affect local protein synthesis. We hypothesize that SMN regulates neurite outgrowth by controlling local protein synthesis through directing the transport of specific mRNAs into the axonal compartment.