Uterine stromal Erbb3-Igf1 signaling is critical to functional gland development conducive to implantation

Abstract Uterine gland branching is a prerequisite for glandular secretion, such as leukemia inhibitory factor (LIF), thereby establishing uterine receptivity to support embryo implantation. Previous studies have demonstrated that epidermal growth factors and their receptors play key roles in mouse pregnancy. Specifically, Uterine deletion of Erbb3 , a member of the ERBB receptor family, using Pgr-Cre ( Erbb3 d/d or Erbb3 f/f Pgr Cre/+ ) results in approximately 70% of plug-positive females failing to deliver any live progeny, whereas uterine epithelial deletion of Erbb3 using Ltf-Cre ( Erbb3 epi/epi or Erbb3 f/f Ltf Cre/+ ) show normal fertility. Here, we identify stromal Erbb3 as a key regulator of uterine gland branching and embryo implantation. Tridimensional visualization reveals that Erbb3 d/d uterine glands lack normal branching, accompanied by reduced in Lif mRNA expression. However, LIF supplementation only partially rescues implantation. Transcriptomic profiling of day 3 stromal cells identified Igf1 as one of the downregulated growth factors in Erbb3 d/d females, implicating its involvement in gland development. Moreover, uterine deletion of Igf1r ( Igf1r f/f Pgr Cre/+ ) leads to a reduced gland branching phenotype similar to that observed in Erbb3 d/d uteri. Together, these results uncover a critical Erbb3-Igf1-Igf1r signaling axis mediating stromal-to-epithelial communication that drives uterine gland branching and ensures successful implantation.