title: Multiple roles of integrin-α3 at the neuromuscular junction.
abstract: The neuromuscular junction (NMJ) is the synapse between motoneurons and skeletal muscle, and is responsible for eliciting muscle contraction. Neurotransmission at synapses depends on the release of synaptic vesicles at sites called active zones (AZs). Various proteins of the extracellular matrix are crucial for NMJ development; however, little is known about the identity and functions of the receptors that mediate their effects. Using genetically modified mice, we find that integrin-α3 (encoded byItga3), an adhesion receptor at the presynaptic membrane, is involved in the localisation of AZ components and efficient synaptic vesicle release. Integrin-α3 also regulates integrity of the synapse - mutant NMJs present with progressive structural changes and upregulated autophagy, features commonly observed during ageing and in models of neurodegeneration. Unexpectedly, we find instances of nerve terminal detachment from the muscle fibre; to our knowledge, this is the first report of a receptor that is required for the physical anchorage of pre- and postsynaptic elements at the NMJ. These results demonstrate multiple roles of integrin-α3 at the NMJ, and suggest that alterations in its function could underlie defects that occur in neurodegeneration or ageing.
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Ross
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Webster
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Tanguy
authors.initials: T
authors.lastname: Lechertier
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Reynolds
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Turmaine
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Bencze
authors.affiliation: Department of Genetics, Institute of Molecular and Clinical Sciences, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Jamshidi
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Hakan
authors.initials: H
authors.lastname: Cetin
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: David
authors.initials: D
authors.lastname: Beeson
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Kairbaan
authors.initials: K
authors.lastname: Hodilvala-Dilke
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK f.conti@ucl.ac.uk.
authors.forename: Francesco J
authors.identifier: 0000-0002-9887-7323
authors.initials: FJ
authors.lastname: Conti
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D047108:Embryonic Development; D039422:Integrin alpha3 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism / Q000648:ultrastructure; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism* / Q000648:ultrastructure; D021381:Protein Transport; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D039422:Integrin alpha3; D002118:Calcium
keywords: Adhesion receptor; Ageing; Autophagy; Neurodegeneration; Synapse