Drosophila Nesprin-1 controls glutamate receptor density at neuromuscular junctions.
Nesprin-1 is a core component of a protein complex connecting nuclei to cytoskeleton termed LINC (linker of nucleoskeleton and cytoskeleton). Nesprin-1 is anchored to the nuclear envelope by its C-terminal KASH domain, the disruption of which has been associated with neuronal and neuromuscular pathologies, including autosomal recessive cerebellar ataxia and Emery-Dreifuss muscular dystrophy. Here, we describe a new and unexpected role of Drosophila Nesprin-1, Msp-300, in neuromuscular junction. We show that larvae carrying a deletion of Msp-300 KASH domain (Msp-300 (∆KASH) ) present a locomotion defect suggestive of a myasthenia, and demonstrate the importance of muscle Msp-300 for this phenotype, using tissue-specific RNAi knock-down. We show that Msp-300 (∆KASH) mutants display abnormal neurotransmission at the larval neuromuscular junction, as well as an imbalance in postsynaptic glutamate receptor composition with a decreased percentage of GluRIIA-containing receptors. We could rescue Msp-300 (∆KASH) locomotion phenotypes by GluRIIA overexpression, suggesting that the locomotion impairment associated with the KASH domain deletion is due to a reduction in junctional GluRIIA. In summary, we found that Msp-300 controls GluRIIA density at the neuromuscular junction. Our results suggest that Drosophila is a valuable model for further deciphering how Nesprin-1 and LINC disruption may lead to neuronal and neuromuscular pathologies.
Equipe Différenciation Neuromusculaire, CNRS, UMR5239, Ecole Normale Supérieure-Lyon, 46 allée d'Italie, 69364, Lyon Cedex 07, France, veronique.morel@ens-lyon.fr.
Véronique
V
Morel
Simon
S
Lepicard
Alexandre N
AN
Rey
Marie-Laure
ML
Parmentier
Laurent
L
Schaeffer
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials; D007814:Larva; D008124:Locomotion; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D010750:Phosphoproteins / Q000172:deficiency / Q000502:physiology; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D008840:Microfilament Proteins; C079806:Msp300 protein, Drosophila; D009124:Muscle Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017470:Receptors, Glutamate; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C062236:dl protein, Drosophila; C077938:cact protein, Drosophila