miR-124 function during Ciona intestinalis neuronal development includes extensive interaction with the Notch signaling pathway.
The 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 Brachyury-regulated notochord genes, as well as several anti-neural factors including SCP1 and PTBP1. 3'UTR 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.
Computational Science Research Center, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA.
Jerry S
JS
Chen
Matthew San
MS
Pedro
Robert W
RW
Zeller
D000818:Animals; D030801:Animals, Genetically Modified; D002938:Ciona intestinalis / Q000196:embryology* / Q000235:genetics; D004625:Embryo, Nonmammalian; D004817:Epidermis / Q000196:embryology / Q000378:metabolism / Q000502:physiology; D004843:Epistasis, Genetic / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009420:Nervous System / Q000196:embryology* / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D035683:MicroRNAs; D051880:Receptors, Notch