Cell
Volume 151, Issue 2, 12 October 2012, Pages 427-439
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Article
SMN Is Required for Sensory-Motor Circuit Function in Drosophila

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Summary

Spinal muscular atrophy (SMA) is a lethal 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 nonautonomously 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. 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 the disease.

Highlights

Drosophila SMN mutants have multiple motor system defects and reduced muscle growth ► Proprioceptive and interneuron SMN rescue corrects motor neuron and muscle defects ► Motor network function is disrupted by SMN depletion subsequent to circuit development ► SMN mutant phenotypes are corrected by increasing motor circuit excitability

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