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bioRxiv · 10.1101/2025.10.16.682855

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

Li, B.·Wang, M.·Dewar, A.·Deng, W.·Dey, S. K.·Sun, X.
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Abstract

Preimplantation uterine gland differentiation, involving glandular branching, is a prerequisite for secretion of leukemia inhibitory factor (LIF), thereby establishing uterine receptivity to embryo implantation. This differentiation process is disrupted by the absence of FOXA2, a transcription factor specifically present in uterine glands. It remains unclear whether preimplantation glandular differentiation is regulated exclusively by gland-intrinsic mechanisms or is influenced by the surrounding microenvironment through mesenchymal-epithelial interactions. We show here that uterine deletion of Erbb3 leads to impaired gland branching and FOXA2 expression, as well as reduced female fertility. In contrast, females with uterine epithelial-specific deletion of Erbb3 show normal fertility, suggesting a critical role of stromal ERBB3 signaling. A transcriptomic profiling of day 3 stromal cells identified Igf1 as a candidate paracrine factor mediating the stromal-epithelial interaction. Thus, the uterine deletion of Igf1r leads to a reduced gland branching phenotype similar to that observed in Erbb3d/d uteri. These results demonstrate that ERBB3 regulates glandular branching and embryo implantation via the ERBB3-IGF1-IGF1R signaling pathway.

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Li, B., Wang, M., Dewar, A., Deng, W., Dey, S. K., Sun, X.. 2025-10-17. Uterine stromal Erbb3-Igf1 signaling is critical to functional gland development conducive to implantation. https://doi.org/10.1101/2025.10.16.682855

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