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

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 (Grb2^d/d). Grb2^d/d mice were infertile due to implantation failure. Although ovarian functions were normal, Grb2^d/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.