title: MuSK frizzled-like domain is critical for mammalian neuromuscular junction formation and maintenance.
abstract: The muscle-specific kinase MuSK is one of the key molecules orchestrating neuromuscular junction (NMJ) formation. MuSK interacts with the Wnt morphogens, through its Frizzled-like domain (cysteine-rich domain [CRD]). Dysfunction of MuSK CRD in patients has been recently associated with the onset of myasthenia, common neuromuscular disorders mainly characterized by fatigable muscle weakness. However, the physiological role of Wnt-MuSK interaction in NMJ formation and function remains to be elucidated. Here, we demonstrate that the CRD deletion of MuSK in mice caused profound defects of both muscle prepatterning, the first step of NMJ formation, and synapse differentiation associated with a drastic deficit in AChR clusters and excessive growth of motor axons that bypass AChR clusters. Moreover, adult MuSKΔCRD mice developed signs of congenital myasthenia, including severe NMJs dismantlement, muscle weakness, and fatigability. We also report, for the first time, the beneficial effects of lithium chloride, a reversible inhibitor of the glycogen synthase kinase-3, that rescued NMJ defects in MuSKΔCRD mice and therefore constitutes a novel therapeutic reagent for the treatment of neuromuscular disorders linked to Wnt-MuSK signaling pathway deficiency. Together, our data reveal that MuSK CRD is critical for NMJ formation and plays an unsuspected role in NMJ maintenance in adulthood.
authors: Centre National de la Recherche Scientifique UMR 8119, Institut National de la Santé et de la Recherche Médicale U686, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris cedex 06 France.
authors: Julien
authors: J
authors: Messéant
authors: Centre National de la Recherche Scientifique UMR 8119, Institut National de la Santé et de la Recherche Médicale U686, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris cedex 06 France.
authors: Alexandre
authors: A
authors: Dobbertin
authors: Centre National de la Recherche Scientifique UMR 5239, Université Lyon 1, ENS, 69364 Lyon cedex 07 France.
authors: Emmanuelle
authors: E
authors: Girard
authors: Centre National de la Recherche Scientifique UMR 8119, Institut National de la Santé et de la Recherche Médicale U686, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris cedex 06 France.
authors: Perrine
authors: P
authors: Delers
authors: Centre National de la Recherche Scientifique UMR 8119, Institut National de la Santé et de la Recherche Médicale U686, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris cedex 06 France.
authors: Marin
authors: http://orcid.org/0000-0002-5344-3572
authors: M
authors: Manuel
authors: EA 2496-PIPA, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris cedex 06 France.
authors: Francesca
authors: F
authors: Mangione
authors: Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France, and.
authors: Alain
authors: A
authors: Schmitt
authors: EA 2496-PIPA, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris cedex 06 France.
authors: Dominique
authors: D
authors: Le Denmat
authors: Centre National de la Recherche Scientifique, Laboratoire de Neurobiologie et Développement, UPR 3294, Gif sur Yvette, Cedex 91198, France.
authors: Jordi
authors: J
authors: Molgó
authors: Centre National de la Recherche Scientifique UMR 8119, Institut National de la Santé et de la Recherche Médicale U686, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris cedex 06 France.
authors: Daniel
authors: D
authors: Zytnicki
authors: Centre National de la Recherche Scientifique UMR 5239, Université Lyon 1, ENS, 69364 Lyon cedex 07 France.
authors: Laurent
authors: L
authors: Schaeffer
authors: Centre National de la Recherche Scientifique UMR 8119, Institut National de la Santé et de la Recherche Médicale U686, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris cedex 06 France.
authors: Claire
authors: C
authors: Legay
authors: Centre National de la Recherche Scientifique UMR 8119, Institut National de la Santé et de la Recherche Médicale U686, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris cedex 06 France, laure.strochlic@inserm.fr.
authors: Laure
authors: http://orcid.org/0000-0001-5373-4284
authors: L
authors: Strochlic
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D005221:Fatigue / Q000235:genetics / Q000503:physiopathology; D005260:Female; D006023:Glycoproteins / Q000737:chemistry*; D018737:Hand Strength / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D018021:Lithium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D018908:Muscle Weakness / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000254:growth & development* / Q000502:physiology* / Q000648:ultrastructure; D011247:Pregnancy; D061251:Primary Cell Culture; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000378:metabolism; D000099274:Frizzled-Related Proteins
chemical_list: D000110:Acetylcholinesterase; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D018021:Lithium Chloride; D020794:Receptor Protein-Tyrosine Kinases; D011950:Receptors, Cholinergic; D000099274:Frizzled-Related Proteins; C511695:MuSK protein, mouse
keywords: MuSK; Wnt; congenital myasthenic syndrome; lithium chloride; neuromuscular junction; synaptogenesis