SMN is required for RNA splicing in sensory-motor circuits. Brian McCabe^1,2, Francesco Lotti¹, Erin Beck^1,2, Ben Choi^1,2, George Mentis¹, Christine Beattie³, Livio Pellizzoni¹, Wendy Imlach^1,2. 1) Pathology & Cell Biology, Columbia University, New York, NY; 2) Neuroscience, Columbia University, New York, NY; 3) Neuroscience, The Ohio State University, Columbus, OH.

   Spinal muscular atrophy (SMA), the most common inherited cause of infant mortality, is a human disease characterized by motor neuron dysfunction and muscle deterioration due to depletion of the ubiquitous Survival Motor Neuron (SMN) protein. Drosophila SMN mutants have reduced muscle size and defective locomotion, motor rhythm and motor neuron neurotransmission. Unexpectedly, restoration of SMN in either muscles or motor neurons did not alter these phenotypes. Instead, SMN must be expressed in proprioceptive neurons and interneurons in the motor circuit to non-autonomously correct defects in motor neurons and muscles. SMN depletion disrupts the motor system subsequent to circuit development and can be mimicked by the inhibition of motor network function. Furthermore, increasing motor circuit excitability by genetic or pharmacological inhibition of K+ channels can correct SMN-dependent phenotypes. In addition, from a genome-wide screen, we have identified a novel protein Stasimon, that has both reduced expression in SMN mutants and can rescue motor circuit activity when restored to normal levels. We find that the regulation of stasimon splicing by SMN is conserved in the motor circuits of both zebrafish and mouse models of SMA. These results establish sensory-motor circuit dysfunction as the origin of motor system deficits in this SMA model and suggest that enhancement of motor neural network activity could ameliorate this RNA splicing disease.