GRB2 regulation of essential signaling pathways in the endometrium is critical for implantation and decidualization

Dinh Nam Tran, Yeon Jeong Hwang, Keun Cheon Kim, Rong Li, Ryan M. Marquardt, Chen Chen, Steven L. Young, Bruce A. Lessey, Tae Hoon Kim, Yong-Pil Cheon () and Jae-Wook Jeong ()
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Dinh Nam Tran: University of Missouri School of Medicine
Yeon Jeong Hwang: Sungshin Women’s University
Keun Cheon Kim: University of Missouri School of Medicine
Rong Li: University of Missouri School of Medicine
Ryan M. Marquardt: Michigan State University
Chen Chen: Michigan State University
Steven L. Young: Duke University
Bruce A. Lessey: Wake Forest Baptist Health
Tae Hoon Kim: University of Missouri School of Medicine
Yong-Pil Cheon: Sungshin Women’s University
Jae-Wook Jeong: University of Missouri School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Over 75% of failed pregnancies involve implantation defects. Growth factor receptor-bound protein 2 (GRB2) is an adaptor protein involved in signal transduction and cell communication. Here we show that the expression of GRB2 protein is lower in endometrium of infertile women with endometriosis compared to controls. Our mouse endometriosis model revealed that endometriosis development results to GRB2 loss in the eutopic endometrium. To understand the role of GRB2 in the uterus, we generated mice with conditional ablation of Grb2 in the Pgr positive cells (Grb2d/d). Grb2d/d mice were infertile due to implantation failure. Although ovarian functions were normal, Grb2d/d mice had a non-receptive endometrium due to progesterone resistance and dysregulation of steroid hormone and FOXA2 signaling pathways. Furthermore, our results were supported by findings of GRB2 attenuation in primary human endometrial stromal cells from women with endometriosis. Our results demonstrate that GRB2 is critical for endometrial receptivity and decidualization.

Date: 2025
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DOI: 10.1038/s41467-025-57173-2

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