title: miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling.
abstract: The transition of dividing neuroepithelial progenitors to differentiated neurons and glia is essential for the formation of a functional nervous system. Sonic hedgehog (Shh) is a mitogen for spinal cord progenitors, but how cells become insensitive to the proliferative effects of Shh is not well understood. Because Shh reception occurs at primary cilia, which are positioned within the apical membrane of neuroepithelial progenitors, we hypothesized that loss of apical characteristics reduces the Shh signaling response, causing cell cycle exit and differentiation. We tested this hypothesis using genetic and pharmacological manipulation, gene expression analysis and time-lapse imaging of zebrafish embryos. Blocking the function of miR-219, a microRNA that downregulates apical Par polarity proteins and promotes progenitor differentiation, elevated Shh signaling. Inhibition of Shh signaling reversed the effects of miR-219 depletion and forced expression of Shh phenocopied miR-219 deficiency. Time-lapse imaging revealed that knockdown of miR-219 function accelerates the growth of primary cilia, revealing a possible mechanistic link between miR-219-mediated regulation of apical Par proteins and Shh signaling. Thus, miR-219 appears to decrease progenitor cell sensitivity to Shh signaling, thereby driving these cells towards differentiation.
authors.affiliation: Departments of Pediatrics and Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Laura I
authors.initials: LI
authors.lastname: Hudish
authors.affiliation: Departments of Pediatrics and Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Domenico F
authors.initials: DF
authors.lastname: Galati
authors.affiliation: Departments of Pediatrics and Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Andrew M
authors.identifier: 0000-0001-8138-3880
authors.initials: AM
authors.lastname: Ravanelli
authors.affiliation: Departments of Pediatrics and Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Chad G
authors.initials: CG
authors.lastname: Pearson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada, T2N 4N1.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Departments of Pediatrics and Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO 80045, USA bruce.appel@ucdenver.edu.
authors.forename: Bruce
authors.identifier: 0000-0003-4500-0672
authors.initials: B
authors.lastname: Appel
mesh_terms: D000818:Animals; D002452:Cell Count; D016764:Cell Polarity; D002923:Cilia / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D038081:Organogenesis; D015398:Signal Transduction; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D035683:MicroRNAs; C524053:Shha protein, zebrafish; D029961:Zebrafish Proteins; C000622225:microRNA-219, zebrafish
keywords: Hedgehog; MicroRNA; Neural progenitors; Polarity; Zebrafish