Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit

Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10660-10665. doi: 10.1073/pnas.1702914114. Epub 2017 Sep 18.


MicroRNAs (miRNAs) have been known to affect various biological processes by repressing expression of specific genes. Here we describe an essential function of the miR-34/449 family during differentiation of epithelial cells. We found that miR-34/449 suppresses the cell-cycle machinery in vivo and promotes cell-cycle exit, thereby allowing epithelial cell differentiation. Constitutive ablation of all six members of this miRNA family causes derepression of multiple cell cycle-promoting proteins, thereby preventing epithelial cells from exiting the cell cycle and entering a quiescent state. As a result, formation of motile multicilia is strongly inhibited in several tissues such as the respiratory epithelium and the fallopian tube. Consequently, mice lacking miR-34/449 display infertility as well as severe chronic airway disease leading to postnatal death. These results demonstrate that miRNA-mediated repression of the cell cycle is required to allow epithelial cell differentiation.

Keywords: cell cycle; ciliogenesis; cyclins; epithelial differentiation; miR-34.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / biosynthesis*
  • Cell Cycle Proteins / genetics
  • Cell Differentiation / physiology*
  • Cell Line
  • Cilia / genetics
  • Cilia / metabolism
  • Fallopian Tubes / cytology
  • Fallopian Tubes / metabolism
  • Female
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism


  • Cell Cycle Proteins
  • MIRN34a microRNA, mouse
  • MicroRNAs
  • Mirn449 microRNA, mouse