title: Wnt proteins contribute to neuromuscular junction formation through distinct signaling pathways.
abstract: Understanding the developmental steps that shape formation of the neuromuscular junction (NMJ) connecting motoneurons to skeletal muscle fibers is crucial. Wnt morphogens are key players in the formation of this specialized peripheral synapse, but their individual and collaborative functions and downstream pathways remain poorly understood at the NMJ. Here, we demonstrate through Wnt4 and Wnt11 gain-of-function studies in cell culture or in mice that Wnts enhance acetylcholine receptor (AChR) clustering and motor axon outgrowth. By contrast, loss of Wnt11 or Wnt-dependent signalingin vivodecreases AChR clustering and motor nerve terminal branching. Both Wnt4 and Wnt11 stimulate AChR mRNA levels and AChR clustering downstream of activation of the β-catenin pathway. Strikingly, Wnt4 and Wnt11 co-immunoprecipitate with Vangl2, a core component of the planar cell polarity (PCP) pathway, which accumulates at embryonic NMJs. Moreover, mice bearing aVangl2loss-of-function mutation (loop-tail) exhibit fewer AChR clusters and overgrowth of motor axons bypassing AChR clusters. Together, our results provide genetic and biochemical evidence that Wnt4 and Wnt11 cooperatively contribute to mammalian NMJ formation through activation of both the canonical and Vangl2-dependent core PCP pathways.
authors.affiliation: CNRS UMR 8119, CNRS UMR 8194, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris 75270 Cedex 06, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Messéant
authors.affiliation: INSERM, Neurocentre Magendie, U1215, Bordeaux 33077, France.|Université de Bordeaux, Neurocentre Magendie, U1215, Bordeaux 33077, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Ezan
authors.affiliation: CNRS UMR 8119, CNRS UMR 8194, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris 75270 Cedex 06, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Delers
authors.affiliation: INSERM, Neurocentre Magendie, U1215, Bordeaux 33077, France.|Université de Bordeaux, Neurocentre Magendie, U1215, Bordeaux 33077, France.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Glebov
authors.affiliation: INSERM U1016, Institut Cochin, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris 75014, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Marchiol
authors.affiliation: INSERM U1016, Institut Cochin, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris 75014, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Lager
authors.affiliation: INSERM U1016, Institut Cochin, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris 75014, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Renault
authors.affiliation: Université Catholique de Louvain, Institute of Neuroscience, Brussels B1200, Belgium.
authors.forename: Fadel
authors.initials: F
authors.lastname: Tissir
authors.affiliation: INSERM, Neurocentre Magendie, U1215, Bordeaux 33077, France.|Université de Bordeaux, Neurocentre Magendie, U1215, Bordeaux 33077, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Montcouquiol
authors.affiliation: INSERM, Neurocentre Magendie, U1215, Bordeaux 33077, France.|Université de Bordeaux, Neurocentre Magendie, U1215, Bordeaux 33077, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sans
authors.affiliation: CNRS UMR 8119, CNRS UMR 8194, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris 75270 Cedex 06, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Legay
authors.affiliation: CNRS UMR 8119, CNRS UMR 8194, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris 75270 Cedex 06, France laure.strochlic@inserm.fr.
authors.forename: Laure
authors.identifier: 0000-0001-5373-4284
authors.initials: L
authors.lastname: Strochlic
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D016764:Cell Polarity; D004622:Embryo, Mammalian / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism*; D010641:Phenotype; D011950:Receptors, Cholinergic / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060528:Wnt4 Protein / Q000378:metabolism*
chemical_list: C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D011950:Receptors, Cholinergic; D051153:Wnt Proteins; C508957:Wnt11 protein, mouse; D060528:Wnt4 Protein
keywords: Mouse; Neuromuscular junction; Planar cell polarity; Vangl2; Wnt; β-catenin signaling