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

Diana Monsivais,Martin M Matzuk,Takashi Nagashima,Se-Jin Lee,Clark Hamor,Suni Tang,Julio E Agno,Francesco J Demayo,Masahito Ikawa,Steven L Young,Fengju Chen,Ramya P Masand,Kaori Nozawa,Renata Prunskaite-Hyyryläinen,Chad J Creighton,Keisuke Shimada

doi:10.1038/s41467-021-23571-5

Abstract

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.

Highlights

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
We provide in vivo evidence underscoring the critical roles of a conserved activin receptor type 2 A (ACVR2A)/ALK3/SMAD1/5 signaling axis during the window of implantation
Previous studies from our group revealed that ALK3 is a critical bone morphogenetic proteins (BMPs) type 1 receptor required for endometrial receptivity in mice and that conditional deletion of ALK3 results in infertility owing to implantation defects[17]

Summary

Introduction

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. BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation. Various cell types are critical in establishing a pregnancy, endometrial epithelial cells participate in maternal–embryonic communication during implantation, and stromal cells transform into a secretory cell type (i.e., decidualize), with the important role of nurturing the growth and development of the early embryo. In vivo studies have shown that conditional deletion of BMP2 or ALK2 results in female infertility owing to defects in the post-implantation process of stromal cell decidualization[8,13]. During the peri-implantation period, BMP signals in the endometrium are mediated via ALK3, and conditional ablation of ALK3 results in infertility due to impaired endometrial receptivity and defective embryo attachment[17]. Our studies identify a link between BMP/ACVR2A/ SMAD1/5 signaling and E2/P4 action in the endometrium during the window of implantation

Methods

Results

Conclusion