Spinal muscular atrophy (SMA) is a devastating motor neuron disease caused by mutations in the SMN1 gene. Reduced levels of SMN protein impair various aspects of neuronal development, particularly axonal growth. However, the molecular mechanisms by which SMN regulates neuronal development remain unclear. In the nucleus, the SMN protein interacts with other proteins essential to RNA biogenesis and splicing. In neurons, SMN protein is localized not only to the nucleus but also to axons and growth cones. In the absence of full-length SMN protein, axons are shorter and growth cones are smaller. From these results we hypothesized that SMN protein plays a role in the transport and processing of the mRNAs necessary for growth, guidance and synapse formation of spinal motor neuron axons. Using mass spectrometry, we demonstrated that SMN interacts with another RNA-binding protein called HuD. Both SMN and HuD proteins interact with cpg15 mRNA in axons. cpg15, originally termed candidate plasticity-related gene 15, increases axon arborization and synapse formation. When SMN protein function is lost, as happens in SMA disease, cpg15 mRNA in the axon decreases. This suggests that cpg15 mRNA is dependent on SMN protein for its location in the axon. We asked whether the reduction of cpg15 may contribute to the formation of short axons in SMN-deficient neurons. To test whether cpg15 could modifier of the SMN-deficiency phenotype, we studied zebrafish that lack functioning SMN and whose axons were shorter and branch abnormally. Over-expression of cpg15 rescued the axon guidance defects in the Smn-deficient zebrafish. These results indicate that cpg15 is an important target of SMN protein in the axon and that replacing cpg15 may offer a potential treatment for SMA.