Spinal muscular atrophy (SMA) is the second most common autosomal recessive inherited disorder in humans, and the most common genetic cause of infant death. It is caused by loss of the survival motor neuron 1 gene(SMN1) but not its copy gene, SMN2. These two virtually identical genes differ by a single nucleotide in exon 7 which alters the activity of an exon 7 splice enhancer. Consequently, a majority of the transcripts from SMN2 lacks exon 7 (delta7 SMN), whereas most of the transcript from SMN1 is full length (FLSMN). The protein product of delta7 SMN is unstable and is rapidly degraded. Thus, SMN2 produces only low levels of SMN protein. Low levels of SMN protein result in motor neuron degeneration, a characteristic feature of SMA. Mice lack SMN2 and a homozygous knockout of murine Stun is embryonic lethal. We have created mouse models of SMA by expressing the human SMN2 gene in mice lacking murine Stun. Mice carrying 1 or 2 copies of the SMN2 transgene on a null Smn background exhibit all of the symptoms of severe (type I) SMA, whereas 8 copies of the SMN2 completely rescue the disease phenotype. This indicates that sufficient SMN protein from SMN2 can prevent motor neuron loss and the disease phenotype. Numerous groups including our own have therefore initiated high through-put drug screens designed to identify molecules capable of stimulating SMN expression from SMN2. We have recently reported one such compound clearly demonstrating the feasibility of the drug screens. However, important questions leading to the eventual treatment of SMA remain. Our aims in this grant are to 1) characterize a mouse model of mild SMA, in order to determine the timing of motor neuron loss, 2) determine at what stage of the disease process high levels of SMN are required to rescue the SMA phenotype, 3) determine in mice whether a phenotypic modifier identified in a related form of SMA (SMA with respiratory distress) also modifies the SMA phenotype and 4) determine whether drug compounds that alter SMN2 expression in cell culture also function in whole animals (in vivo). The results of this proposal are hoped to act as a transition to an effective treatment of SMA.