miR-219 Regulates Neural Precursor Differentiation by Direct Inhibition of Apical Par Polarity Proteins

• Published in: Developmental cell 2013-11, Vol.27 (4), p.387-398
• Main Authors: Hudish, Laura I., Blasky, Alex J., Appel, Bruce
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Cycle; Cell Differentiation; Cell Polarity; Cell Proliferation; Danio rerio; Immunoenzyme Techniques; In Situ Hybridization; Luciferases - metabolism; MicroRNAs - genetics; Neurogenesis - genetics; Neurons - cytology; Neurons - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Stem Cells - cytology; Stem Cells - metabolism; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2013.10.015

Asymmetric self-renewing division of neural precursors is essential for brain development. Partitioning-defective (Par) proteins promote self-renewal, and their asymmetric distribution provides a mechanism for asymmetric division. Near the end of neural development, most asymmetric division ends and precursors differentiate. This correlates with Par protein disappearance, but mechanisms that cause downregulation are unknown. MicroRNAs can promote precursor differentiation but have not been linked to Par protein regulation. We tested a hypothesis that microRNA miR-219 promotes precursor differentiation by inhibiting Par proteins. Neural precursors in zebrafish larvae lacking miR-219 function retained apical proteins, remained in the cell cycle, and failed to differentiate. miR-219 inhibited expression via target sites within the 3′ untranslated sequence of pard3 and prkci mRNAs, which encode Par proteins, and blocking miR-219 access to these sites phenocopied loss of miR-219 function. We propose that negative regulation of Par protein expression by miR-219 promotes cell-cycle exit and differentiation. [Display omitted] •miR-219 regulates neural precursor maintenance and specification•miR-219 inhibits expression of pard3 and prkci via 3′ UTR target sites•miR-219 reduction interferes with neuronal and glial cell differentiation The transition from self-renewing neural precursor division to neuronal and glial cell differentiation is an important step in development. Hudish et al. show in zebrafish that miR-219-mediated negative regulation of apical Par proteins, which help maintain self-renewing neural precursors, promotes cell-cycle exit and differentiation.