MuSK Frizzled-Like Domain Is Critical for Mammalian Neuromuscular Junction Formation and Maintenance

• DOI: 10.1523/jneurosci.3381-14.2015
• Publication Date: 2015-03-25T16:21:08Z
• 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
• Keywords: MESH: Fatigue; Male; 0301 basic medicine; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; MESH: Animals, Newborn; Mice; MESH: Pregnancy; Pregnancy; MESH: Animals; [SDV.BDD]Life Sciences [q-bio]/Development Biology; Fatigue; MuSK; Motor Neurons; synaptogenesis; Muscle Weakness; neuromuscular junction; [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior; Hand Strength; Intracellular Signaling Peptides and Proteins; MESH: Muscle Weakness; [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences; MESH: Lithium Chloride; MESH: Hand Strength; Acetylcholinesterase; MESH: Receptor Protein-Tyrosine Kinases; Female; MESH: Motor Neurons; MESH: Myasthenic Syndromes, Congenital; MESH: Mutation; MESH: Mice, Transgenic; Primary Cell Culture; MESH: Glycoproteins; Neuromuscular Junction; Mice, Transgenic; MESH: Primary Cell Culture; Wnt; 03 medical and health sciences; Animals; MESH: Mice; lithium chloride; Glycoproteins; Myasthenic Syndromes, Congenital; MESH: Receptors, Cholinergic; Receptor Protein-Tyrosine Kinases; MESH: Acetylcholinesterase; MESH: Male; Animals, Newborn; congenital myasthenic syndrome; Mutation; MESH: Neuromuscular Junction; Lithium Chloride; MESH: Female

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, adultMuSKΔCRDmice 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 inMuSKΔCRDmice 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.