The coregulator, repressor of estrogen receptor activity (REA), is a crucial regulator of the timing and magnitude of uterine decidualization

Yuechao Zhao, Sunghee Park, Milan K Bagchi, Robert N. Taylor, Benita S Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

Successful implantation and maintenance of pregnancy require the transformation of uterine endometrial stromal cells into distinct decidualized cells. Although estrogen and progesterone (P4) receptors are known to be essential for decidualization, the roles of steroid receptor coregulators in this process remain largely unknown. In this study, we have established a key role for the coregulator, repressor of estrogen receptor activity (REA), in the decidualization of human endometrial stromal cells (hESCs) in vitro and of the mouse uterus in vivo. Our studies revealed that the level ofREAnormally decreases to half as hESC decidualization proceedsandthat uterine reduction of REA in transgenic heterozygous knockout mice or small interfering RNA knockdown of REA in hESC temporally accelerated and strongly enhanced the differentiation process, as indicated by changes in cell morphology and increased expression of biomarkers of decidualization, including P4 receptor. Findings in hESC cultured in vitro with estradiol, P4, and 8-bromo-cAMP over a 10-day period mirrored observations of enhanced decidualization response in transgenic mice with heterozygous deletion of REA. Importantly, gene expression and immunohistochemical analyses revealed changes in multiple components of the Janus kinase/signal transducer and activator of transcription pathway, including marked up-regulation of signal transducer and activator of transcription 3 and IL-11, master regulators of decidualization, and the down-regulation of several suppressor of cytokine signaling family members, upon reduction of REA. The findings highlight that REA physiologically restrains endometrial stromal cell decidualization, controlling the timing and magnitude of decidualization to enable proper coordination of uterine differentiation with concurrent embryo development that is essential for implantation and optimal fertility.

Original languageEnglish (US)
Pages (from-to)1349-1360
Number of pages12
JournalEndocrinology
Volume154
Issue number3
DOIs
StatePublished - Mar 1 2013

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Stromal Cells
Estrogen Receptors
Pregnancy Maintenance
Interleukin-11
Janus Kinases
8-Bromo Cyclic Adenosine Monophosphate
STAT3 Transcription Factor
Steroid Receptors
Progesterone Receptors
Transducers
Human Activities
Knockout Mice
Small Interfering RNA
Transgenic Mice
Uterus
Embryonic Development
Fertility
Estradiol
Estrogens
Up-Regulation

ASJC Scopus subject areas

  • Endocrinology

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The coregulator, repressor of estrogen receptor activity (REA), is a crucial regulator of the timing and magnitude of uterine decidualization. / Zhao, Yuechao; Park, Sunghee; Bagchi, Milan K; Taylor, Robert N.; Katzenellenbogen, Benita S.

In: Endocrinology, Vol. 154, No. 3, 01.03.2013, p. 1349-1360.

Research output: Contribution to journalArticle

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