Irx3 promotes gap junction communication between uterine stromal cells to regulate vascularization during embryo implantation

Abstract

Appropriate embryo-uterine interactions are essential for implantation. Besides oocyte abnormalities, implantation failure is a major contributor to early pregnancy loss. Previously, we demonstrated that two members of the Iroquois homeobox transcription factor family, IRX3 and IRX5, exhibited distinct and dynamic expression profiles in the developing ovary to promote oocyte and follicle survival. Elimination of each gene independently caused subfertility, but with different breeding pattern outcomes. Irx3 KO (Irx3LacZ/LacZ) females produced fewer pups throughout their reproductive lifespan which could only be partially explained by poor oocyte quality. Thus, we hypothesized that IRX3 is also expressed in the uterus where it acts to support pregnancy. To test this hypothesis, we harvested pregnant uteri from control and Irx3 KO females to evaluate IRX3 expression profiles and the integrity of embryo implantation sites. Our results indicate that IRX3 is expressed in the endometrial stromal cells at day 4 of pregnancy (D4) with peak expression at D5-6, and then greatly diminishes by D7. Further, histology and immunofluorescence at D7 showed that while embryos were able to attach to the uterus, implantation sites in Irx3 KO pregnant mice exhibited impaired vascularization, abnormal expression of decidualization markers, and disruptions in GJA1 organization in the decidual bed. Finally, we also observed an impaired response of the Irx3 KO uteri to an artificial deciduogenic stimulus, indicating a critical role of this factor in regulating the decidualization program. Together, these data established that IRX3 promotes female fertility via at least two different mechanisms: 1) promoting competent oocytes and 2) facilitating functional embryo-uterine interactions during implantation.

Mechanisms of theFTOlocus association with obesity: Irx3 controls a sumoylation-dependent switch between adipogenesis and osteogenesis

“…For example, our data show that Irx3 controls genes in the Wnt/β-catenin and Hippo signaling pathways in preadipocytes, and these pathways have been shown by others to also be regulated by Irx3 and/or Irx5 in kidney development [41]. Thus our data may help understand how IRX3 mediates its effects in several other conditions in which IRX3 has been implicated, including type 2 diabetes [10], metabolic inflammation [42], fertility [43], neurogenesis [44,45], glioblastoma [46], acute myeloid leukemia [47–50], microvascularization [51] and heart development and function [52– 57].…”