Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure

Science. 2015 Dec 18;350(6267):1525-9. doi: 10.1126/science.aad2509.

Abstract

Dysfunction of microRNA (miRNA) metabolism is thought to underlie diseases affecting motoneurons. One miRNA, miR-218, is abundantly and selectively expressed by developing and mature motoneurons. Here we show that mutant mice lacking miR-218 die neonatally and exhibit neuromuscular junction defects, motoneuron hyperexcitability, and progressive motoneuron cell loss, all of which are hallmarks of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Gene profiling reveals that miR-218 modestly represses a cohort of hundreds of genes that are neuronally enriched but are not specific to a single neuron subpopulation. Thus, the set of messenger RNAs targeted by miR-218, designated TARGET(218), defines a neuronal gene network that is selectively tuned down in motoneurons to prevent neuromuscular failure and neurodegeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation*
  • Gene Regulatory Networks
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Motor Neuron Disease / genetics*
  • Motor Neuron Disease / physiopathology
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Motor Neurons / physiology*
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / pathology
  • Spinal Cord / metabolism
  • Spinal Cord / physiopathology

Substances

  • MIRN218 microRNA, mouse
  • MicroRNAs