First author David Simon and colleagues found that miR-1 attenuates expression of C. elegans unc-29 and unc-63, genes that encode nicotinic acetylcholine receptor (nAChR) subunits. When miR-1 is mutated, the overexpression of the nAChR subunits somehow decreases the sensitivity of the neuromuscular junction to levamisole, an agonist of the C. elegans nAChR. Exactly how the receptor sensitivity is altered is not clear. The authors suggest several possibilities, including perturbations of associations with accessory subunits, altered receptor assembly in the endoplasmic reticulum, compromised trafficking to the cell surface, or simply functional changes of the mature receptor once it gets to the surface.

The miRNA does not stop at modifying the acetylcholine receptor. Simon and colleagues found that it also attenuates presynaptic acetylcholine release. At first blush this might appear quite unexpected, given that miR-1 is expressed only in muscle, but the authors found that it is involved in a retrograde signaling pathway that feeds back across the synapse and tones down acetylcholine release from presynaptic terminals. This retrograde signaling depends on the transcription factor MEF-2. Interestingly, mammalian Mef2A modulates the formation of excitatory synapses on both hippocampal and cerebellar neurons (see ARF related news story), though it is not clear how. “We speculate that Mef2 effects on synapse formation in hippocampal neurons may be mediated by retrograde inhibition of synaptic inputs, leading to their elimination,” write the authors. Kaplan told ARF via e-mail that it is possible that a different miRNA might be involved in retrograde inhibition in the CNS, “but I have no guess as to which microRNA that would be, nor how likely that scenario is,” he wrote.

Simon and colleagues found that on the presynaptic side of the neuromuscular junction, the retrograde signaling initiated by miR-1 leads to a decrease in the activity of Rab3, the small GTPase that associates with synaptic vesicles. Both Mef2 signaling pathways and Rab3 have been linked to amyloid precursor protein (see Burton et al., 2002, and ARF related news story).—Tom Fagan.

Reference:
Simon DJ, Madison JM, Conery AL, Thompson-Peer KL, Soskis M, Ruvkun GB, Kaplan JM, Kim JK. The microRNA miR-1 regulates a MEF-2-dependent retrograde signal at neuromuscular junctions. Cell 2008 May 30; 133: 903-915. Abstract