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Updated: Feb 17, 2026
Establishing 3D Endometrial Organoids from the Mouse Uterus
Published on: January 6, 2023
LEFTY2 inhibits endometrial receptivity by downregulating Orai1 expression and store-operated Ca2+ entry
Madhuri S Salker1, Yogesh Singh2, Ruban R Peter Durairaj3
1Department of Women's Health, Eberhard-Karls University Tuebingen, Calwerstr 7, D-72076, Tuebingen, Germany.
Abstract:
Early embryo development and endometrial differentiation are initially independent processes, and synchronization, imposed by a limited window of implantation, is critical for reproductive success. A putative negative regulator of endometrial receptivity is LEFTY2, a member of the transforming growth factor (TGF)-β family. LEFTY2 is highly expressed in decidualizing human endometrial stromal cells (HESCs) during the late luteal phase of the menstrual cycle, coinciding with the closure of the window of implantation. Here, we show that flushing of the uterine lumen in mice with recombinant LEFTY2 inhibits the expression of key receptivity genes, including Cox2, Bmp2, and Wnt4, and blocks embryo implantation. In Ishikawa cells, a human endometrial epithelial cell line, LEFTY2 downregulated the expression of calcium release-activated calcium channel protein 1, encoded by ORAI1, and inhibited store-operated Ca2+ entry (SOCE). Furthermore, LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, as well as YM-58483, inhibited, whereas the Ca2+ ionophore, ionomycin, strongly upregulated COX2, BMP2 and WNT4 expression in decidualizing HESCs. These findings suggest that LEFTY2 closes the implantation window, at least in part, by downregulating Orai1, which in turn limits SOCE and antagonizes expression of Ca2+-sensitive receptivity genes.
Key Messages:
•Endometrial receptivity is negatively regulated by LEFTY2. •LEFTY2 inhibits the expression of key murine receptivity genes, including Cox2, Bmp2 and Wnt4, and blocks embryo implantation. •LEFTY2 downregulates the expression of Orai1 and inhibits SOCE. •LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, and YM-58483 inhibit COX2, BMP2, and WNT4 expression in endometrial cells. •Targeting LEFTY2 and Orai1 may represent a novel approach for treating unexplained infertility.
Insights
LEFTY2 negatively regulates endometrial receptivity by downregulating Orai1 and inhibiting calcium entry, thereby closing the implantation window. Targeting LEFTY2 and Orai1 may offer new treatments for unexplained infertility.
Area of Science:
- Reproductive biology and endocrinology
- Cellular and molecular mechanisms of implantation
Background:
- Successful reproduction hinges on the synchronization between early embryo development and endometrial differentiation, governed by a narrow window of implantation.
- LEFTY2, a transforming growth factor (TGF)-β family member, is highly expressed in human endometrial stromal cells during the late luteal phase, coinciding with implantation window closure.
Purpose of the Study:
- To investigate the role of LEFTY2 as a negative regulator of endometrial receptivity and its underlying molecular mechanisms.
- To explore the potential of targeting LEFTY2 and Orai1 for treating unexplained infertility.
Main Methods:
- Administration of recombinant LEFTY2 in a murine model to assess its effect on uterine receptivity genes and embryo implantation.
- In vitro studies using Ishikawa cells and human endometrial stromal cells (HESCs) to evaluate LEFTY2's impact on Orai1 expression, store-operated calcium entry (SOCE), and key receptivity genes (COX2, BMP2, WNT4).
- Utilized Orai1 blockers (2-APB, MRS-1845, YM-58483) and a calcium ionophore (ionomycin) to elucidate the role of calcium signaling.
Main Results:
- Recombinant LEFTY2 administration in mice inhibited key receptivity genes (Cox2, Bmp2, Wnt4) and blocked embryo implantation.
- In human endometrial cells, LEFTY2 downregulated Orai1 expression and inhibited store-operated calcium entry (SOCE).
- LEFTY2 and Orai1 blockers suppressed COX2, BMP2, and WNT4 expression in decidualizing HESCs, while ionomycin upregulated them, confirming the role of calcium signaling.
Conclusions:
- LEFTY2 acts as a negative regulator of endometrial receptivity, contributing to the closure of the implantation window.
- This inhibitory effect is mediated, at least in part, by the downregulation of Orai1, leading to reduced SOCE and antagonism of calcium-sensitive receptivity gene expression.
- Targeting the LEFTY2-Orai1 pathway presents a potential novel therapeutic strategy for managing unexplained infertility.
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