miR-34/449 miRNAs Are Required for Motile Ciliogenesis by Repressing cp110

Nature. 2014 Jun 5;510(7503):115-20. doi: 10.1038/nature13413.

Abstract

The mir-34/449 family consists of six homologous miRNAs at three genomic loci. Redundancy of miR-34/449 miRNAs and their dominant expression in multiciliated epithelia suggest a functional significance in ciliogenesis. Here we report that mice deficient for all miR-34/449 miRNAs exhibited postnatal mortality, infertility and strong respiratory dysfunction caused by defective mucociliary clearance. In both mouse and Xenopus, miR-34/449-deficient multiciliated cells (MCCs) exhibited a significant decrease in cilia length and number, due to defective basal body maturation and apical docking. The effect of miR-34/449 on ciliogenesis was mediated, at least in part, by post-transcriptional repression of Cp110, a centriolar protein suppressing cilia assembly. Consistent with this, cp110 knockdown in miR-34/449-deficient MCCs restored ciliogenesis by rescuing basal body maturation and docking. Altogether, our findings elucidate conserved cellular and molecular mechanisms through which miR-34/449 regulate motile ciliogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Basal Bodies / metabolism
  • Basal Bodies / pathology
  • Basal Bodies / ultrastructure
  • Base Sequence
  • Calmodulin-Binding Proteins / deficiency*
  • Calmodulin-Binding Proteins / genetics*
  • Calmodulin-Binding Proteins / metabolism
  • Centrioles / metabolism
  • Cilia / genetics*
  • Cilia / pathology
  • Cilia / physiology*
  • Cilia / ultrastructure
  • Epidermis / embryology
  • Epidermis / pathology
  • Female
  • Infertility / genetics
  • Infertility / physiopathology
  • Kartagener Syndrome / genetics
  • Kartagener Syndrome / pathology
  • Kartagener Syndrome / physiopathology
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Morphogenesis / genetics*
  • Phenotype
  • Respiratory System / pathology
  • Respiratory System / physiopathology
  • Survival Analysis
  • Xenopus laevis / embryology

Substances

  • Calmodulin-Binding Proteins
  • Cp110 protein, mouse
  • MIRN34a microRNA, mouse
  • MicroRNAs
  • Mirn449 microRNA, mouse