Abstract
The autosomal recessive neuromuscular disorder associated with the enervated (enr) mouse transgene insertion manifests impaired peripheral nerve regeneration due to defects in Schwann cells and resembles the myodystrophy (Largemyd) phenotype. Here we show that the enr transgene has integrated into Chr 8 approximately 160 kb downstream from the 3′ end of the Large gene disrupting its expression as confirmed by the lack of genetic complementation between Largemyd and enr mice, the very low Large mRNA levels in enr tissues and hypoglycosylation of α-dystroglycan, a known substrate of LARGE. Mutant nerve conduction and grip strength were impaired whereas sodium channel clustering at the nodes of Ranvier was unaffected. Interestingly, the mutant neuromuscular junctions displayed abnormal acetylcholine receptor clustering with reduced immunostaining for β-dystroglycan, laminin, agrin, MuSK, and to a lesser extent acetylcholinesterase and rapsyn. These data implicate LARGE in nerve, muscle, and neuromuscular junction function.
Original language | English (US) |
---|---|
Pages (from-to) | 757-769 |
Number of pages | 13 |
Journal | Molecular and Cellular Neuroscience |
Volume | 28 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2005 |
Funding
We would like to thank Drs. Stanley C. Froehner, Jean-Antoine Girault, and Kevin P. Campbell for providing the antibodies to rapsyn, paranodin/Caspr, and core α-dystroglycan, respectively. Also, we wish to thank Nicole Campbell for initiating the histology, electrophysiology, and behavioral experiments; Victoria Yan for her contribution to electron microscopy; and Hanson Ho for performing the electrophysiology, grip strength tests, and morphometric analyses. This work was supported by a grant from the National Institutes of Health to BP (NS27336).
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Molecular Biology
- Cell Biology