An SMN-dependent U12 splicing event essential for motor circuit function.
Spinal muscular atrophy (SMA) is a motor neuron disease caused by deficiency of the ubiquitous survival motor neuron (SMN) protein. To define the mechanisms of selective neuronal dysfunction in SMA, we investigated the role of SMN-dependent U12 splicing events in the regulation of motor circuit activity. We show that SMN deficiency perturbs splicing and decreases the expression of a subset of U12 intron-containing genes in mammalian cells and Drosophila larvae. Analysis of these SMN target genes identifies Stasimon as a protein required for motor circuit function. Restoration of Stasimon expression in the motor circuit corrects defects in neuromuscular junction transmission and muscle growth in Drosophila SMN mutants and aberrant motor neuron development in SMN-deficient zebrafish. These findings directly link defective splicing of critical neuronal genes induced by SMN deficiency to motor circuit dysfunction, establishing a molecular framework for the selective pathology of SMA.
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
Francesco
F
Lotti
Wendy L
WL
Imlach
Luciano
L
Saieva
Erin S
ES
Beck
Le T
le T
Hao
Darrick K
DK
Li
Wei
W
Jiao
George Z
GZ
Mentis
Christine E
CE
Beattie
Brian D
BD
McCabe
Livio
L
Pellizzoni
D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000378:metabolism*; D041681:NIH 3T3 Cells; D012342:RNA, Small Nuclear / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D008565:Membrane Proteins; D012342:RNA, Small Nuclear; D016601:RNA-Binding Proteins; C542563:Smn protein, Drosophila; C577002:Stas protein, Drosophila; C577003:Tmem41b protein, mouse; C577004:Tmem41b protein, zebrafish; C096986:U12 small nuclear RNA; D029961:Zebrafish Proteins