Spinal Muscular Atrophy: Is it a motor axon disease?

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Spinal muscular atrophy (SMA) is an autosomal recessive disease and one of the leading causes of infant mortality. To elucidate the biological mechanism underlying this motoneuron disease, SMA has been modeled in mice and zebrafish. Low levels of the Survival Motor Neuron (SMN) protein are the cause of SMA. The earliest phenotype associated with low SMN levels in zebrafish is motor axon defects (truncations and aberrant branching). These defects are specific and cell-autonomous for motor axons and occur in the absence of motoneuron cell death. This, and data from others showing that SMN is transported down axons to growth cones, indicates that SMA is a motor axon disease. The experiments outlined in this proposal directly test this possibility. First, the functional and behavioral consequences of ectopic motor axon branching in zebrafish will be addressed. Individual fish with defined motor axon defects will be analyzed for movement defects and decreased life span. To address directly whether defective motor axons lead to motoneuronal cell death, neuromuscular junctions, synaptic activity, and motoneuron survival will be analyzed for individual hemisegments with defective nerves. Secondly, whether SMN depletion in mice causes motor axon branching will be examined by analyzing axonal outgrowth into the intercostal, diaphragm, and limb muscles. In addition, it will be determined when in development SMN function is needed to rescue motor axon defects and the SMA phenotype. Lastly, SMN complexes have been implicated in RNA transport and are present in growth cones suggesting that SMN may function in localizing RNAs to growth cones for localized protein translation. Using a reverse genetic approach in zebrafish to deplete proteins shown to complex with SMN in motor axons will reveal whether decreasing these proteins also leads to motor axon defects and motoneuronal cell death. Zebrafish motor axons will also be used to directly test whether localized protein translation is affected when SMN levels are decreased using beta-actin as a candidate protein. Experiments outlined in this proposal will directly test the hypothesis that SMA is a motor axon disease and will reveal whether SMN functions in a complex crucial for localized protein translation in motor axon growth cones.