Abstract
During neuronal circuit formation, axons progressively develop into a presynaptic compartment aided by extracellular signals. Axons display a remarkably high degree of autonomy supported in part by a local translation machinery that permits the subcellular production of proteins required for their development. Here, we review the latest findings showing that microRNAs (miRNAs) are critical regulators of this machinery, orchestrating the spatiotemporal regulation of local translation in response to cues. We first survey the current efforts toward unraveling the axonal miRNA repertoire through miRNA profiling, and we reveal the presence of a putative axonal miRNA signature. We also provide an overview of the molecular underpinnings of miRNA action. Our review of the available experimental evidence delineates two broad paradigms: cue-induced relief of miRNA-mediated inhibition, leading to bursts of protein translation, and cue-induced miRNA activation, which results in reduced protein production. Overall, this review highlights how a decade of intense investigation has led to a new appreciation of miRNAs as key elements of the local translation regulatory network controlling axon development.
Highlights
During neuronal circuit assembly, the distal tip of the growing axon navigates a complex environment and reaches its target where it branches and establishes connections with the synaptic partners
While it was known that mRNA translation is triggered asymmetrically within the growth cone in relation to the side of cue exposure [5,6], recent studies revealed additional focal hotspots of de novo protein synthesis appear at sites of branch emergence, on RAB7A endosomes, and in association with mitochondria [16,17,18]
A developing axon displays a large degree of autonomy and relies in part on local mRNA translation to promote its growth, steering, targeting, branching, and synaptogenesis, which are all critical steps in neuronal circuit development
Summary
The distal tip of the growing axon navigates a complex environment and reaches its target where it branches and establishes connections with the synaptic partners Each of these phases of axon development is largely controlled by extracellular signals that induce local cytoskeletal remodeling. Its tip becomes distant from the cell body and can no longer rely on the soma to promptly supply the proteins that it needs for its development To overcome this challenge, the axon progressively acquires a high degree of autonomy that enables it to independently manufacture its building blocks. MiRNAs constitute a large category of short, non-coding RNAs that play widespread regulatory roles in post-transcriptional steps of gene expression, mainly affecting mRNA stability and translation [19] They act essentially as specificity determinants for effector proteins, which are represented by Argonautes (AGOs) in eukaryotes. We will explore how the axon critically exploits miRNAs to ensure that a subset of mRNAs are selected for translation locally on demand into proteins that promotes its outgrowth, steering, and branching
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