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 hasbeen 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 MuSK⌬CRD 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 MuSK⌬CRD 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.

Muscle Yap Is a Regulator of Neuromuscular Junction Formation and Regeneration

“…Inhibition of glycogen synthase kinase 3␤ activates ␤-catenin signaling. LiCl has been used recently to determine Wnt canonical pathway in NMJ formation (Messéant et al, 2015). We used this method to determine whether ␤-catenin activation mitigates NMJ formation deficits in HSA-Yap Ϫ/Ϫ mice.…”

Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution

“…A recent study reported that prepatterned AChRs were almost undetectable and that synapse formation and motor performance were severely impaired in mice that are mutant for the MuSK Fz-like domain (Messéant et al 2015). However, Messéant et al (2015) did not examine the patterning of AChR expression prior to or independent of innervation.…”

“…A recent study reported that prepatterned AChRs were almost undetectable and that synapse formation and motor performance were severely impaired in mice that are mutant for the MuSK Fz-like domain (Messéant et al 2015). However, Messéant et al (2015) did not examine the patterning of AChR expression prior to or independent of innervation. Even at the earliest stage examined by Messéant et al (2015), motor axons had innervated the diaphragm muscle, precluding investigation of the role of the MuSK Fz-like domain in muscle prepatterning.…”

“…However, Messéant et al (2015) did not examine the patterning of AChR expression prior to or independent of innervation. Even at the earliest stage examined by Messéant et al (2015), motor axons had innervated the diaphragm muscle, precluding investigation of the role of the MuSK Fz-like domain in muscle prepatterning. It is unclear what accounts for the strikingly differing findings on synapse formation and motor performance reported here and in the study from Messéant et al (2015).…”

“…Even at the earliest stage examined by Messéant et al (2015), motor axons had innervated the diaphragm muscle, precluding investigation of the role of the MuSK Fz-like domain in muscle prepatterning. It is unclear what accounts for the strikingly differing findings on synapse formation and motor performance reported here and in the study from Messéant et al (2015). We note that the MuSK ΔFz mutant described in Messéant et al (2015) lacked amino acids 305-453 and was substantially overexpressed, as the 85-kDa mutant protein was shown to be much more abundant than the ∼110-kDa wild-type protein.…”