TY - JOUR T1 - MuSK Frizzled-Like Domain Is Critical for Mammalian Neuromuscular Junction Formation and Maintenance JF - The Journal of Neuroscience JO - J. Neurosci. SP - 4926 LP - 4941 DO - 10.1523/JNEUROSCI.3381-14.2015 VL - 35 IS - 12 AU - Julien Messéant AU - Alexandre Dobbertin AU - Emmanuelle Girard AU - Perrine Delers AU - Marin Manuel AU - Francesca Mangione AU - Alain Schmitt AU - Dominique Le Denmat AU - Jordi Molgó AU - Daniel Zytnicki AU - Laurent Schaeffer AU - Claire Legay AU - Laure Strochlic Y1 - 2015/03/25 UR - http://www.jneurosci.org/content/35/12/4926.abstract N2 - 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. ER -