Gli3 is required for glandular epithelial proliferation and endometrial homeostasis during the estrous cycle

Abstract

The endometrium is the innermost compartment of the uterus and undergoes cyclical remodeling throughout the human menstrual cycle and the rodent estrous cycle. The endometrium must thicken appropriately for embryonic implantation to occur; thus, it is crucial to understand the molecular mechanisms downstream of steroid hormone action that regulate endometrial thickness. Hedgehog (Hh) signaling is required for endometrial remodeling in both mice and humans, but the role of downstream Hh transcriptional effectors in endometrial remodeling is unknown. Here, we discover a role for the Hh transcriptional repressor, Gli3, in endometrial homeostasis: conditional knockout of Gli3 resulted in a constitutively thick endometrium throughout the estrous cycle. In our model, a constitutively thick endometrium could support pregnancy. Bulk RNA-sequencing data revealed that loss of Gli3 also resulted in dysregulated stromal-epithelial crosstalk, while immunofluorescent staining showed larger uterine glands and increased gland proliferation. These data deepen our understanding of molecular mechanisms controlling endometrial thickness, offering novel pathways to investigate endometrial factors in infertility.