Endometrial receptivity and implantation require uterine BMP signaling through an ACVR2A-SMAD1/SMAD5 axis

Nat Commun. 2021 Jun 7;12(1):3386. doi: 10.1038/s41467-021-23571-5.


During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents embryo implantation and leads to infertility. Analysis of Acvr2a-PRcre and Acvr2b-PRcre pregnant mice determined that BMP signaling occurs via ACVR2A and that ACVR2B is dispensable during embryo implantation. Therefore, BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / metabolism
  • Animals
  • Biopsy
  • Bone Morphogenetic Proteins / metabolism*
  • Disease Models, Animal
  • Embryo Implantation*
  • Endometrium / metabolism
  • Endometrium / pathology
  • Estrogens / metabolism
  • Female
  • Humans
  • Infertility, Female / genetics*
  • Mice
  • Mice, Knockout
  • Pregnancy
  • Signal Transduction / physiology
  • Smad1 Protein / analysis
  • Smad1 Protein / genetics
  • Smad1 Protein / metabolism
  • Smad5 Protein / analysis
  • Smad5 Protein / genetics
  • Smad5 Protein / metabolism


  • Bone Morphogenetic Proteins
  • Estrogens
  • SMAD1 protein, human
  • SMAD5 protein, human
  • Smad1 Protein
  • Smad1 protein, mouse
  • Smad5 Protein
  • Smad5 protein, mouse
  • Activin Receptors, Type II
  • activin receptor type II-A
  • activin receptor type II-B