title: Dystrophin is required for appropriate retrograde control of neurotransmitter release at the Drosophila neuromuscular junction.
abstract: Mutations in the human dystrophin gene cause the Duchenne and Becker muscular dystrophies. The Dystrophin protein provides a structural link between the muscle cytoskeleton and extracellular matrix to maintain muscle integrity. Recently, Dystrophin has also been found to act as a scaffold for several signaling molecules, but the roles of dystrophin-mediated signaling pathways remain unknown. To further our understanding of this aspect of the function of dystrophin, we have generated Drosophila mutants that lack the large dystrophin isoforms and analyzed their role in synapse function at the neuromuscular junction. In expression and rescue studies, we show that lack of the large dystrophin isoforms in the postsynaptic muscle cell leads to elevated evoked neurotransmitter release from the presynaptic apparatus. Overall synapse size, the size of the readily releasable vesicle pool as assessed with hypertonic shock, and the number of presynaptic neurotransmitter release sites (active zones) are not changed in the mutants. Short-term synaptic facilitation of evoked transmitter release is decreased in the mutants, suggesting that the absence of dystrophin results in increased probability of release. Absence of the large dystrophin isoforms does not lead to changes in muscle cell morphology or alterations in the postsynaptic electrical response to spontaneously released neurotransmitter. Therefore, postsynaptic glutamate receptor function does not appear to be affected. Our results indicate that the postsynaptically localized scaffolding protein Dystrophin is required for appropriate control of neuromuscular synaptic homeostasis.
authors.affiliation: Department of Molecular and Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Mariska C
authors.initials: MC
authors.lastname: van der Plas
authors.forename: Gonneke S K
authors.initials: GS
authors.lastname: Pilgram
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Plomp
authors.forename: Anja
authors.initials: A
authors.lastname: de Jong
authors.forename: Lee G
authors.initials: LG
authors.lastname: Fradkin
authors.forename: Jasprina N
authors.initials: JN
authors.lastname: Noordermeer
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics; D016189:Dystrophin / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D016189:Dystrophin; D018377:Neurotransmitter Agents