Retinoic acid receptor signaling orchestrates uterine receptivity, decidual competence, and immune homeostasis during early pregnancy

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Abstract

Successful implantation requires precise coordination of uterine epithelial receptivity, stromal decidualization, and immune homeostasis during a narrow peri-implantation window. Although retinoic acid (RA) signaling has been implicated in female reproduction, the endogenous and isoform-specific roles of retinoic acid receptors (RARs) remain poorly defined. Here, we combined isoform-specific genetic mouse models, transcriptomic profiling, and functional studies in mouse and human stromal cells to determine how RAR signaling regulates early pregnancy. We found that RARG is the dominant RAR isoform required for female fertility in mice, as its deletion severely impaired implantation, whereas combined loss of all RAR isoforms caused complete reproductive failure. RAR deficiency disrupted multiple sequential reproductive processes, including sperm transport and fertilization, suppression of uterine estrogen receptor activity, acquisition of stromal decidualization competence, and maintenance of uterine immune homeostasis. Transcriptomic analyses identified conserved epithelial and mesenchymal programs altered across independent RAR-deficient mouse models and revealed significant overlap with endometrial gene signatures from women with recurrent implantation failure. In human endometrial stromal cells, suppression of the RARA isoform consistently disrupted decidualization across three independent primary cell lines and an immortalized cell model. Together, these findings identify RAR signaling as a critical regulator of early pregnancy and reveal conserved, isoform-specific functions required for early pregnancy.

Authors

Yan Yin, Emily Y. So, Eliana Wolf, Vivian Robles Pinos, Meade Haller, Renjie Shang, Sylvia C. Hewitt, Alex Tak, Brent M. Bany, David Y. Chen, Mengcheng Shen, Francesco J. DeMayo, Liang Ma