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 journalArticle

166 Citations (Scopus)

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

Fingerprint

Progesterone Receptors
MicroRNAs
Pregnancy
Down-Regulation
Tissue Array Analysis
Oxytocin Receptors
Homeodomain Proteins
Gene Expression
Connexin 43
Premature Obstetric Labor
Zinc Fingers
Premature Birth
Oxytocin
Uterus
Progesterone
Carrier Proteins
Up-Regulation
Genes

Keywords

  • Lipopolysaccharide
  • Myometrium
  • Parturition
  • RU486

ASJC Scopus subject areas

  • General

Cite this

MiR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. / Renthal, Nora E.; Chen, Chien Cheng; Williams, Koriand'R C.; Gerard, Robert D.; Prange-Kiel, Janine; Mendelson, Carole R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 48, 30.11.2010, p. 20828-20833.

Research output: Contribution to journalArticle

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