title: Modeling spinal muscular atrophy in Drosophila.
abstract: Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Howard Chia-Hao
authors.initials: HC
authors.lastname: Chang
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Dimlich
authors.forename: Takakazu
authors.initials: T
authors.lastname: Yokokura
authors.forename: Ashim
authors.initials: A
authors.lastname: Mukherjee
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kankel
authors.forename: Anindya
authors.initials: A
authors.lastname: Sen
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Sridhar
authors.forename: Tudor A
authors.initials: TA
authors.lastname: Fulga
authors.forename: Anne C
authors.initials: AC
authors.lastname: Hart
authors.forename: David
authors.initials: D
authors.lastname: Van Vactor
authors.forename: Spyros
authors.initials: S
authors.lastname: Artavanis-Tsakonas
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D004331:Drosophila melanogaster; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D009469:Neuromuscular Junction / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D013569:Synapses / Q000378:metabolism
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