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

Tobias Otto, Sheyla V. Candido, Mary S. Pilarz, Ewa Sicinska, Roderick T. Bronson, Michaela Bowden, Iga A. Lachowicz, Kristin Mulry, Anne Fassl, Richard C. Han, Emmanuelle S. Jecrois, Piotr Sicinski

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)10660-10665
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number40
DOIs
StatePublished - 3 Oct 2017
Externally publishedYes

Keywords

  • Cell cycle
  • Ciliogenesis
  • Cyclins
  • Epithelial differentiation
  • miR-34

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