miR-124 function during Ciona intestinalis neuronal development includes extensive interaction with the Notch signaling pathway

Abstract

SUMMARYThe nervous system-enriched microRNA miR-124 is necessary for proper nervous system development, although the mechanism remains poorly understood. Here, through a comprehensive analysis of miR-124 and its gene targets, we demonstrate that, in the chordate ascidian Ciona intestinalis, miR-124 plays an extensive role in promoting nervous system development. We discovered that feedback interaction between miR-124 and Notch signaling regulates the epidermal-peripheral nervous system (PNS) fate choice in tail midline cells. Notch signaling silences miR-124 in epidermal midline cells, whereas in PNS midline cells miR-124 silences Notch, Neuralized and all three Ciona Hairy/Enhancer-of-Split genes. Furthermore, ectopic expression of miR-124 is sufficient to convert epidermal midline cells into PNS neurons, consistent with a role in modulating Notch signaling. More broadly, genome-wide target extraction with validation using an in vivo tissue-specific sensor assay indicates that miR-124 shapes neuronal progenitor fields by downregulating non-neural genes, notably the muscle specifier Macho-1 and 50 Brachyuryregulated notochord genes, as well as several anti-neural factors including SCP1 and PTBP1. 3ЈUTR conservation analysis reveals that miR-124 targeting of SCP1 is likely to have arisen as a shared, derived trait in the vertebrate/tunicate ancestor and targeting of PTBP1 is conserved among bilaterians except for ecdysozoans, while extensive Notch pathway targeting appears to be Ciona specific. Altogether, our results provide a comprehensive insight into the specific mechanisms by which miR-124 promotes neuronal development.

Capturing microRNA targets using an RNA-induced silencing complex (RISC)-trap approach

“…Of note, these two transcripts were not identified as miR-132 targets by HITS-CLIP in murine brain (8). MicroRNA-124 targets Ctdsp1 and PTBP1-both identified in this screen-have known roles in the embryonic development of the central nervous system in chick and mouse, as well as the nervous system development in Ciona intestinalis (50)(51)(52). The top candidate target in our miR-124 screen was RhoG, which showed an ∼20-fold enrichment.…”

Evolution of the chordate regeneration blastema: Differential gene expression and conserved role of notch signaling during siphon regeneration in the ascidian Ciona

“…Siphon regeneration involves the regrowth and/or differentiation of severed nerve tracts (Auger et al, 2010). Since Notch signaling was previously shown to be involved in central and peripheral nervous system development in ascidian embryos and larvae (Akanuma et al, 2002; Pasini et al, 2006; Hudson et al, 2007; Chen et al, 2011), the possible function of the Notch pathway during adult neural regeneration would be an important subject for future study. Furthermore, during the Ciona life span, the capacity for regeneration continuously declines until it is compromised near the end of life (Dahlberg et al, 2009; Auger et al, 2010; Jeffery, 2012).…”

The Role of miRNAs in the Development of Normal Pancreas and Pancreatic Cancer, and Their Roles in Tumor Progression

“…In addition, the activity of Hedgehog signaling has been found to be regulated by several miRNAs. Studies have shown that miR-212, miR-214, miR-196, and miR-17-92 cluster could regulate Hedgehog signaling [24][25][26][27], suggesting that these miRNAs could participate in the development of pancreas.…”