Steroid receptor coactivator-2 drives epithelial reprogramming that enables murine embryo implantation

Vineet K Maurya1, Maria M Szwarc1, David M Lonard1

  • 1Department of Molecular and Cellular Biology, Center for Coregulator Research, Baylor College of Medicine, Houston, Texas, USA.

Insights

Steroid receptor coactivator-2 (SRC-2) is crucial for embryo implantation by enabling uterine receptivity. Loss of SRC-2 prevents embryo attachment, highlighting its role in early pregnancy establishment.

Area of Science:

  • Reproductive Biology
  • Molecular Endocrinology
  • Cellular Biology

Background:

  • Steroid receptor coactivator-2 (SRC-2) is known to be essential for decidualization in endometrial stromal cells.
  • The role of SRC-2 in earlier stages of embryo implantation, specifically in the uterine luminal epithelium, remains inadequately addressed.
  • Uterine receptivity is a critical prerequisite for successful embryo implantation and establishment of early pregnancy.

Purpose of the Study:

  • To investigate the role of endometrial SRC-2 in the critical early stages of embryo implantation.
  • To determine if SRC-2 is required for the plasma membrane transformation (PMT) state necessary for uterine receptivity.
  • To elucidate the molecular mechanisms by which SRC-2 influences uterine receptivity and implantation.

Main Methods:

  • Utilized a conditional SRC-2 knockout mouse model (SRC-2d/d) in timed natural pregnancy studies.
  • Examined embryo attachment and adherence to the uterine luminal epithelium in SRC-2d/d and control mice.
  • Assessed the expression of Mucin 1 and E-cadherin in the luminal epithelium.
  • Performed transcriptomic analysis to identify gene expression changes in the SRC-2d/d endometrium.

Main Results:

  • Endometrial SRC-2 is essential for embryo attachment and adherence to the uterine luminal epithelium.
  • SRC-2d/d mice exhibit implantation failure associated with persistent apical Mucin 1 and basolateral E-cadherin expression.
  • The SRC-2d/d luminal epithelium fails to undergo the plasma membrane transformation (PMT) required for uterine receptivity.
  • Transcriptomics revealed disrupted expression of genes involved in steroid hormone control, epithelial tight junctions, and epithelial-mesenchymal transition (EMT) in SRC-2d/d endometrium.

Conclusions:

  • Endometrial SRC-2 plays a novel and critical role in inducing the luminal epithelial PMT state.
  • This SRC-2-dependent PMT is a prerequisite for establishing uterine receptivity and successful early pregnancy.
  • SRC-2 regulates key molecular pathways, including those controlling epithelial integrity and plasticity, essential for implantation.

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