miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor — PNAS

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

1. Nora E. Renthala,b,
2. Chien-Cheng Chena,b,
3. Koriand'r C. Williamsa,b,
4. Robert D. Gerardc,
5. Janine Prange-Kield, and
6. Carole R. Mendelsona,b,e,1

+ Author Affiliations

1. Departments of aBiochemistry,
2. eObstetrics and Gynecology,
3. cInternal Medicine, and
4. dCell Biology,
5. bNorth Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, TX 75390

1. Edited* by Bert W. O'Malley, Baylor College of Medicine, Houston, TX, and approved October 14, 2010 (received for review June 16, 2010)

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 down-regulated 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 contraction-associated 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.

Footnotes

* 1To whom correspondence should be addressed. E-mail: carole.mendelson@utsouthwestern.edu.
* Author contributions: N.E.R. and C.R.M. designed research; N.E.R., C.-C.C., and J.P.-K. performed research; N.E.R., K.C.W., and R.D.G. contributed new reagents/analytic tools; N.E.R. and C.R.M. analyzed data; and N.E.R. and C.R.M. wrote the paper.
* The authors declare no conflict of interest.
* ↵*This Direct Submission article had a prearranged editor.
* Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE25017).
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1008301107/-/DCSupplemental.

miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor — PNAS



GINECOLOGÍA
Identifican un mecanismo molecular implicado en las contracciones del parto
Actualidad Ultimas noticias - JANOes -
JANO.es · 17 Noviembre 2010 00:09

El hallazgo podría convertirse en una diana farmacológica para prevenir el parto prematuro.


Investigadores de la University of Texas Southwestern Medical Center, Estados Unidos, han identificado un mecanismo molecular que interviene en las contracciones del parto y que podría convertirse en una diana farmacológica para prevenir el parto prematuro. Los resultados del estudio se publican en la revista Proceedings of the National Academy of Sciences (PNAS).

La investigación muestra que existen pequeños fragmentos de ARN, llamados microARN, que podrían actuar como activadores genéticos en los tejidos uterinos al forzar al útero a contraerse durante el parto. Los autores del trabajo sabían ya que hormonas como la progesterona y la oxitocina, juegan un papel clave en el embarazo y el parto. Sin embargo, los científicos conocían poco sobre los mecanismos de señalización que subyacen a la transformación de la pared uterina muscular, llamada miometrio, de un tejido inactivo a una masa en contracción.

Los científicos, dirigidos por Carole R. Mendelson, utilizaron análisis de la expresión genética para desvelar un bucle de señalización de retroalimentación en el que intervienen los microARN miR-200 y sus proteínas diana, ZEB1 y ZEB2, que ayuda a contraerse al miometrio en respuesta a las señales que inducen el parto. Según muestran los investigadores, mientras que los niveles de los microARN en el miometrio de ratones y humanos se elevan cuando se contrae el útero, los niveles de ZEB1 y ZEB2 caen.

Durante el embarazo, los niveles elevados de progesterona circulante ayudan aumentar los niveles de ZEB1 en el miometrio, mientras que cerca de la fecha de término, los niveles de ZEB1 en el útero de ratones y humanos se desploman. Además, en las células de miometrio humano producidas en el laboratorio, ZEB1 y ZEB2 reducen la síntesis de proteínas vinculadas a la contracción, bloqueando la contracción del músculo uterino inducida por la oxitocina.

Los descubrimientos arrojan luz sobre los mecanismos que subyacen a la contracción uterina y proporcionan información para prevenir el parto prematuro, una importante causa de muerte neonatal.


PNAS 2010;doi:10.1073/pnas.1008301107
miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor — PNAS

University of Texas Southwestern Medical Center
University of Texas Southwestern Medical Center at Dallas

Actualidad Ultimas noticias - JANOes - Identifican un mecanismo molecular implicado en las contracciones del parto - JANO.es - ELSEVIER