A Drosophila melanogaster model of spinal muscular atrophy reveals a function for SMN in striated muscle.
Mutations in human survival motor neurons 1 (SMN1) cause spinal muscular atrophy (SMA) and are associated with defects in assembly of small nuclear ribonucleoproteins (snRNPs) in vitro. However, the etiological link between snRNPs and SMA is unclear. We have developed a Drosophila melanogaster system to model SMA in vivo. Larval-lethal Smn-null mutations show no detectable snRNP reduction, making it unlikely that these animals die from global snRNP deprivation. Hypomorphic mutations in Smn reduce dSMN protein levels in the adult thorax, causing flightlessness and acute muscular atrophy. Mutant flight muscle motoneurons display pronounced axon routing and arborization defects. Moreover, Smn mutant myofibers fail to form thin filaments and phenocopy null mutations in Act88F, which is the flight muscle-specific actin isoform. In wild-type muscles, dSMN colocalizes with sarcomeric actin and forms a complex with alpha-actinin, the thin filament crosslinker. The sarcomeric localization of Smn is conserved in mouse myofibrils. These observations suggest a muscle-specific function for SMN and underline the importance of this tissue in modulating SMA severity.
Rajendra
T K
TK
Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Gonsalvez
Graydon B
GB
Walker
Michael P
MP
Shpargel
Karl B
KB
Salz
Helen K
HK
Matera
A Gregory
AG
D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009210:Myofibrils / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism; D055532:SMN Complex Proteins; D012518:Sarcomeres / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein
D000199:Actins; D017362:Cyclic AMP Response Element-Binding Protein; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D000185:Actinin