SMN is required for sensory-motor circuit function in Drosophila.
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.
Center for Motor Neuron Biology and Disease, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.
Wendy L
WL
Imlach
Erin S
ES
Beck
Ben Jiwon
BJ
Choi
Francesco
F
Lotti
Livio
L
Pellizzoni
Brian D
BD
McCabe
D000818:Animals; D059329:Cholinergic Neurons / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007814:Larva / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000378:metabolism; D009154:Mutation; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism
D029721:Drosophila Proteins; D016601:RNA-Binding Proteins; C542563:Smn protein, Drosophila