title: Loss of glial neurofascin155 delays developmental synapse elimination at the neuromuscular junction.
abstract: Postnatal synapse elimination plays a critical role in sculpting and refining neural connectivity throughout the central and peripheral nervous systems, including the removal of supernumerary axonal inputs from neuromuscular junctions (NMJs). Here, we reveal a novel and important role for myelinating glia in regulating synapse elimination at the mouse NMJ, where loss of a single glial cell protein, the glial isoform of neurofascin (Nfasc155), was sufficient to disrupt postnatal remodeling of synaptic circuitry. Neuromuscular synapses were formed normally in mice lacking Nfasc155, including the establishment of robust neuromuscular synaptic transmission. However, loss of Nfasc155 was sufficient to cause a robust delay in postnatal synapse elimination at the NMJ across all muscle groups examined. Nfasc155 regulated neuronal remodeling independently of its canonical role in forming paranodal axo-glial junctions, as synapse elimination occurred normally in mice lacking the axonal paranodal protein Caspr. Rather, high-resolution proteomic screens revealed that loss of Nfasc155 from glial cells was sufficient to disrupt neuronal cytoskeletal organization and trafficking pathways, resulting in reduced levels of neurofilament light (NF-L) protein in distal axons and motor nerve terminals. Mice lacking NF-L recapitulated the delayed synapse elimination phenotype observed in mice lacking Nfasc155, suggesting that glial cells regulate synapse elimination, at least in part, through modulation of the axonal cytoskeleton. Together, our study reveals a glial cell-dependent pathway regulating the sculpting of neuronal connectivity and synaptic circuitry in the peripheral nervous system.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XF, United Kingdom, Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Roche
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Sherman
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XF, United Kingdom, Clinical Pharmacology Unit, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Kosala
authors.initials: K
authors.lastname: Dissanayake
authors.affiliation: Research Centre of Centre Hospitalier Universitaire de Québec, Department of Psychiatry and Neurosciences, Laval University, Québec F-3471, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Soucy
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Desmazieres
authors.affiliation: FingerPrints Proteomics Facility, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Douglas J
authors.identifier: http://orcid.org/0000-0002-2262-5680
authors.initials: DJ
authors.lastname: Lamont
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, POB 26, Rehovot 76100, Israel, and.
authors.forename: Elior
authors.initials: E
authors.lastname: Peles
authors.affiliation: Research Centre of Centre Hospitalier Universitaire de Québec, Department of Psychiatry and Neurosciences, Laval University, Québec F-3471, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
authors.affiliation: Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom, Division of Neurobiology, Roslin Institute and Royal Dick School of Veterinary Studies, University of Edinburgh, Edinburgh, EH25 9RG, United Kingdom.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wishart
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XF, United Kingdom, Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Ribchester
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XF, United Kingdom, Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom, T.Gillingwater@ed.ac.uk.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009045:Motor Endplate / Q000254:growth & development; D009046:Motor Neurons / Q000378:metabolism; D009414:Nerve Growth Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D009431:Neural Conduction / Q000235:genetics / Q000502:physiology; D016900:Neurofilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009469:Neuromuscular Junction / Q000254:growth & development / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics; D040901:Proteomics; D012583:Schwann Cells / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; C504593:Nfasc protein, mouse; D020033:Protein Isoforms; C044882:neurofilament protein L
keywords: Schwann cell; glia; neurofascin; neuromuscular junction; peripheral nervous system; synapse elimination