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

• Published in: Nature communications Vol. 12; no. 1; p. 3386
• Main Authors: Monsivais, Diana, Nagashima, Takashi, Prunskaite-Hyyryläinen, Renata, Nozawa, Kaori, Shimada, Keisuke, Tang, Suni, Hamor, Clark, Agno, Julio E., Chen, Fengju, Masand, Ramya P., Young, Steven L., Creighton, Chad J., DeMayo, Francesco J., Ikawa, Masahito, Lee, Se-Jin, Matzuk, Martin M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 07.06.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Ablation; Activin; Bone morphogenetic proteins; Cell signaling; Deletion; Embryos; Endometrium; Epithelium; Estrogens; Females; Fertility; Gene expression; Implantation; Infertility; Medical schools; Medicine; Ovaries; Pregnancy; Progesterone; Receptors; Signal transduction; Signaling; Smad5 protein; Uterus
• ISSN: 2041-1723; 2041-1723
• 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.