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

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 p...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 40; pp. 10660 - 10665
Main Authors Otto, Tobias, Candido, Sheyla V., Pilarz, Mary S., Sicinska, Ewa, Bronson, Roderick T., Bowden, Michaela, Lachowicz, Iga A., Mulry, Kristin, Fassl, Anne, Han, Richard C., Jecrois, Emmanuelle S., Sicinski, Piotr
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 03.10.2017
Subjects
Biological activity
Biological Sciences
Cell cycle
Cell differentiation
Derepression
Differentiation (biology)
Epithelial cells
Epithelium
Fallopian tube
Gene expression
Genes
Infertility
Machinery and equipment
MicroRNAs
miRNA
Proteins
Respiratory tract diseases
Rodents
epithelial differentiation
cell cycle
ciliogenesis
miR-34
cyclins
Online AccessGet full text
ISSN0027-8424
1091-6490
1091-6490
DOI10.1073/pnas.1702914114

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Summary: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.
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Author contributions: T.O. and P.S. designed research; T.O., S.V.C., M.S.P., E.S., M.B., I.A.L., K.M., A.F., R.C.H., and E.S.J. performed research; T.O., E.S., R.T.B., M.B., and P.S. analyzed data; and T.O. and P.S. wrote the paper.
1Present address: Department of Internal Medicine III, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen 52074, Germany.
Edited by Terry L. Orr-Weaver, Whitehead Institute, Cambridge, MA, and approved August 24, 2017 (received for review February 22, 2017)
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1702914114