Diana Monsivais1,2, Takashi Nagashima3,4, Renata Prunskaite-Hyyryläinen5, Kaori Nozawa3,6, Keisuke Shimada7, Suni Tang3, Clark Hamor3, Julio E Agno3,6, Fengju Chen8, Ramya P Masand3, Steven L Young9, Chad J Creighton8,10, Francesco J DeMayo11, Masahito Ikawa7, Se-Jin Lee12,13, Martin M Matzuk14,15. 1. Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. dmonsiva@bcm.edu. 2. Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA. dmonsiva@bcm.edu. 3. Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. 4. Hanakoganei Ladies Clinic, Tokyo, Japan. 5. Faculty of Biochemistry and Medicine, University of Oulu, Oulu, Finland. 6. Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA. 7. Research Institute for Microbial Disease, Osaka University, Osaka, Japan. 8. Department of Medicine, Baylor College of Medicine, Houston, TX, USA. 9. Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, USA. 10. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. 11. National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. 12. Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. 13. University of Connecticut School of Medicine, Department of Genetics and Genome Sciences, Farmington, CT, USA. 14. Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. mmatzuk@bcm.edu. 15. Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA. mmatzuk@bcm.edu.
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.
During early pregnancy ihemical">n the n class="Species">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.
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