Spinal muscular Atrophy (SMA) is an autosomal recessive disease that can cause infant mortality. SMA is caused by the loss, or mutation, of the Survival Motor Neuron 1 gene (SMN1) and retention of the SMN2 gene. Both genes are ubiquitously expressed, but the majority of the product from the SMN2 gene lacks exon 7. This results in the SMN2 gene producing insufficient SMN protein for the correct function of motor neurons. The severity of the phenotype is modulated by SMN protein levels, which is influenced by the copy number of the SMN2 gene.
The aim of this proposal is to determine what factors activate SMN expression, which tissue, muscle or nerve requires high levels of SMN and whether a genetic system capable of identifying the critical function of SMN for motor neurons can be developed. This will help address the question: Why does deficiency of SMN cause a motor neuron disorder? We will determine what is required for activation of SMN expression by identifying the transcription factors that bind the SMN promoter. We will determine what tissue requires high levels of SMN by making mice that express SMN in either muscle or motor neurons, and asking which of these mouse lines can correct the SMA phenotype. This experiment will also address whether motor neurons are uniquely sensitive to SMN levels. The SMN levels will not be restored in non-cholinergic neurons. If SMN's splicing function is impaired due to low levels of the protein, these cells should degenerate. To develop a genetic model system which can be used in suppressor screens, which are capable of identifying the critical function of SMN in motor neurons, we are developing a zebrafish model of SMA. The zebrafish SMA model will also allow precise studies on the motor neuron development in SMA. The grant will define the transcriptional targets, which could be used for treatment of SMA, the tissue that requires high levels of SMN and will give a genetic system to define the function lacking in SMA. These developments will be important in developing treatments for SMA.
