MiR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor

Nora E. Renthal, Chien Cheng Chen, Koriand'R C. Williams, Robert D. Gerard, Janine Prange-Kiel, Carole R. Mendelson

Research output: Contribution to journalArticlepeer-review

183 Scopus citations

Abstract

Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. In this study, we uncovered a previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as hormonally modulated and conserved mediators of contraction-associated genes in the pregnant uterus in the mouse and human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans as well as two coordinately downregulated targets, zinc finger E-box binding homeobox proteins ZEB1 and ZEB2, which act as transcriptional repressors. We also observed up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P4)/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contractionassociated genes, oxytocin receptor and connexin-43, and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets, ZEB1 and ZEB2, as unique P4/PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor and shed light on the molecular mechanisms involved in preterm birth.

Original languageEnglish (US)
Pages (from-to)20828-20833
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number48
DOIs
StatePublished - Nov 30 2010

Keywords

  • Lipopolysaccharide
  • Myometrium
  • Parturition
  • RU486

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'MiR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor'. Together they form a unique fingerprint.

Cite this