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: Julien Messéant, Alexandre Dobbertin, Emmanuelle Girard, Perrine Delers, Marin Manuel, Francesca Mangione, Alain Schmitt, Dominique Le Denmat, Jordi Molgó, Daniel Zytnicki, Laurent Schaeffer, Claire Legay, Laure Strochlic
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 35 Issue 12 Pg. 4926-41 (Mar 25 2015) ISSN: 1529-2401 [Electronic] United States
• PMID: 25810523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the authors 0270-6474/15/354926-16$15.00/0.

Chemical References

• Glycoproteins
• Intracellular Signaling Peptides and Proteins
• Receptors, Cholinergic
• WD repeat containing planar cell polarity effector
• MuSK protein, mouse
• Receptor Protein-Tyrosine Kinases
• Acetylcholinesterase
• Lithium Chloride

Topics

• Acetylcholinesterase (metabolism)
• Animals
• Animals, Newborn
• Fatigue (genetics, physiopathology)
• Female
• Glycoproteins (chemistry)
• Hand Strength (physiology)
• Intracellular Signaling Peptides and Proteins
• Lithium Chloride (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Transgenic
• Motor Neurons (drug effects, physiology)
• Muscle Weakness (drug therapy, genetics, physiopathology)
• Mutation
• Myasthenic Syndromes, Congenital (drug therapy, genetics, physiopathology)
• Neuromuscular Junction (drug effects, growth & development, physiology, ultrastructure)
• Pregnancy
• Primary Cell Culture
• Receptor Protein-Tyrosine Kinases (chemistry, genetics, physiology)
• Receptors, Cholinergic (metabolism)