Drosophila Nesprin-1 controls glutamate receptor density at neuromuscular junctions |
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Authors: | Véronique Morel Simon Lepicard Alexandre N Rey Marie-Laure Parmentier Laurent Schaeffer |
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Institution: | 1. Equipe Différenciation Neuromusculaire, CNRS, UMR5239, Ecole Normale Supérieure-Lyon, 46 allée d’Italie, 69364, Lyon Cedex 07, France 2. Institut de Génomique Fonctionnelle, CNRS, UMR5203, 141 rue de la cardonille, 34094, Montpellier Cedex 05, France 3. INSERM, U.661, Université Montpellier 1,2, Montpellier, France 4. Université Lyon 1, Villeurbanne, France 5. Centre de biotechnologies cellulaires, Hospices civils de Lyon, Lyon, France
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Abstract: | 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. |
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