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

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 used 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 implantation through persistent estrogen receptor activity, loss of stromal decidualization competence, and induction of a pathological inflammatory state. RAR-deficient uterine gene expression programs showed strong overlap with those observed in women with recurrent implantation failure, supporting clinical relevance.