Abstract
Retinoic acid (RA) is the biologically active metabolite of vitamin A and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By miRNA sequencing analysis, we identify 482 miRNAs in the regenerating central nervous system (CNS) of the mollusc Lymnaea stagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up- or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate, for the first time, that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (pedal A), whereas expression in the growth cones of another class of respiratory motorneurons (right parietal A) was absent in vitro. These findings support our hypothesis that miRNAs are important regulators of retinoic acid-induced neuronal outgrowth and regeneration in regeneration-competent species.
Highlights
Following injury to the central nervous system (CNS), the ability of damaged neurons to repair and regenerate functional connections is limited in most species
We performed the first transcriptome analysis of miRNAs expressed during CNS regenIenrathtiiosnstiundtyh,ewienvpeerrtfeobrmraeted, tLhyemfinrasetatrsatnagscnrailpist.omLeymannaaleyasiiss oaf umsieRfuNlAmsoedxeplreosrsgeadndisumrinfogrCtNheS srteugdeyneorfaatidounltinCtNheSirnevgeernteebraratitoen, Ldyumentaoeaitsstaegxnteanliss.ivLeymrengaeenaeirsaatiuvseecfuapl macoitdye, laonrdgaenasisemoffoisrotlhaetiostnudoyf of adult CNS regeneration due to its extensive regenerative capacity, and ease of isolation of large, identifiable neurons for cell culture
We identified 483 miRNAs in the adult Lymnaea CNS, and discovered a specific subset that may contribute to retinoic acid (RA)-induced regeneration
Summary
Following injury to the central nervous system (CNS), the ability of damaged neurons to repair and regenerate functional connections is limited in most species. Many trophic and chemotropic factors that mediate neuronal outgrowth and connectivity in regeneration-competent species are highly conserved and functional in many vertebrates and invertebrates [3,4,5]. RA signaling mediates neuronal outgrowth [6] and differentiation [7] during both CNS development and regeneration [8,9,10] To exert such effects, RA binds to two classes of nuclear receptors, the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). We identified miRNAs in the regenerating CNS of adult Lymnaea and discovered a specific subset that were either upregulated or downregulated during RA-induced neurite sprouting. We examined the spatial distribution of miR-124 in regenerating motorneurons, and demonstrated a cell-specific expression in regenerating growth cones
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