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PLoS One. 2014 Mar 24;9(3):e93140. doi: 10.1371/journal.pone.0093140. eCollection 2014.

The role of muscle microRNAs in repairing the neuromuscular junction.

Author information

1
Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America; Virginia Tech Carilion Research Institute, Virginia Tech, Roanoke, Virginia, United States of America.
2
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Molecular Therapeutics, The Scripps Research Institute Florida, Jupiter, Florida, United States of America.
3
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States of America; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
4
Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America.

Abstract

microRNAs have been implicated in mediating key aspects of skeletal muscle development and responses to diseases and injury. Recently, we demonstrated that a synaptically enriched microRNA, miR-206, functions to promote maintenance and repair of the neuromuscular junction (NMJ); in mutant mice lacking miR-206, reinnervation is impaired following nerve injury and loss of NMJs is accelerated in a mouse model of amyotrophic lateral sclerosis (ALS). Here, we asked whether other microRNAs play similar roles. One attractive candidate is miR-133b because it is in the same transcript that encodes miR-206. Like miR-206, miR-133b is concentrated near NMJs and induced after denervation. In miR-133b null mice, however, NMJ development is unaltered, reinnervation proceeds normally following nerve injury, and disease progression is unaffected in the SOD1(G93A) mouse model of ALS. To determine if miR-206 compensates for the loss of miR-133b, we generated mice lacking both microRNAs. The phenotype of these double mutants resembled that of miR-206 single mutants. Finally, we used conditional mutants of Dicer, an enzyme required for the maturation of most microRNAs, to generate mice in which microRNAs were depleted from skeletal muscle fibers postnatally, thus circumventing a requirement for microRNAs in embryonic muscle development. Reinnervation of muscle fibers following injury was impaired in these mice, but the defect was similar in magnitude to that observed in miR-206 mutants. Together, these results suggest that miR-206 is the major microRNA that regulates repair of the NMJ following nerve injury.

PMID:
24664281
PMCID:
PMC3963997
DOI:
10.1371/journal.pone.0093140
[Indexed for MEDLINE]
Free PMC Article

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