The dystrophin Dp186 isoform regulates neurotransmitter release at a central synapse in Drosophila.
The Dystrophin protein is encoded by a gene that, when mutated in humans, can cause Duchenne muscular dystrophy, a disease characterized by progressive muscle wasting. A number of Duchenne patients also exhibit poorly understood mental retardation, likely associated with loss of a brain-specific isoform. Furthermore, although Dystrophin isoforms and the related Utrophin protein have long been known to localize at synapses, their functions remain essentially unknown. In Drosophila, we find that the CNS-specific Dp186 isoform localizes to the embryonic and larval neuropiles, regions rich in synaptic contacts. In the absence of Dp186, evoked but not spontaneous presynaptic release is significantly enhanced. Increased presynaptic release can be fully rescued to wild-type levels by expression of a Dp186 transgene in the postsynaptic motoneuron, indicating that Dp186 likely regulates a retrograde signaling pathway. Potentiation of synaptic currents in the mutant also occurs when cholinergic transmission is inhibited or in the absence of Glass Bottom Boat (Gbb) or Wishful Thinking (Wit), a TGF-beta ligand and receptor, respectively, both previously implicated in synaptic retrograde signaling. These results are consistent with the possibility that Dp186 modulates other non-Gbb/Wit-dependent retrograde signaling pathways required to maintain normal synaptic physiology.
Fradkin
Lee G
LG
Laboratory of Developmental Neurobiology, Department of Molecular and Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. L.G.Fradkin@lumc.nl
Baines
Richard A
RA
van der Plas
Mariska C
MC
Noordermeer
Jasprina N
JN
D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004553:Electric Conductivity; D004625:Embryo, Nonmammalian / Q000378:metabolism; D007814:Larva / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology; D009154:Mutation; D019581:Neuropil / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D029721:Drosophila Proteins; D016189:Dystrophin; D018377:Neurotransmitter Agents; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C089440:gbb protein, Drosophila; C449821:wit protein, Drosophila