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

Science  18 Dec 2015:
Vol. 350, Issue 6267, pp. 1525-1529
DOI: 10.1126/science.aad2509

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The makings of motor neuron disease

Developing motor neurons link the muscles to the central nervous system. Amin et al. found that microRNA-218 (miR-218) was expressed in developing motor neurons and repressed a wide network of genes whose expression typifies other sorts of neurons. Mice lacking miR-218 died at birth with symptoms characteristic of human motor neuron diseases.

Science, this issue p. 1525

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 target218, defines a neuronal gene network that is selectively tuned down in motoneurons to prevent neuromuscular failure and neurodegeneration.

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