Rasgrp1-Mediated Dampening of EGFR Signals Supports Coordinated Mammary Gland Development.

Mammary gland development during puberty requires tightly coordinated epithelial proliferation, lineage specification, and branching morphogenesis, processes critically regulated by growth factor signaling. While epidermal growth factor receptor (EGFR) signaling is essential for ductal development, how its activity is quantitatively controlled within mammary epithelial cells (MECs) remains incompletely understood. Here, we identify Rasgrp1, a Ras guanine nucleotide exchange factor, as a key modulator of EGFR signaling in the mammary epithelium. Using Rasgrp1-deficient mice, primary MEC assays, and organoid models, we demonstrate that loss of Rasgrp1 leads to elevated EGFR-Ras-PI3K-AKT and mTORC1-S6 signaling, resulting in enhanced proliferative capacity and aberrant EGF-driven branching. Transcriptomic analysis of organoids reveals that EGF signaling suppresses Wnt/R-spondin-dependent stem-cell gene programs, suggesting that excessive EGFR activity disrupts stem cell maintenance. In vivo, Rasgrp1 deficiency causes impaired ductal elongation, persistent terminal end buds, and increased epithelial proliferation, indicating a breakdown in the spatial and temporal coordination of mammary morphogenesis. Together, our findings establish Rasgrp1 as a signaling rheostat that dampens EGFR pathway activity to support coordinated mammary gland development. These results highlight the importance of precise signaling calibration in epithelial development and suggest broader implications for Ras pathway regulation in tissue homeostasis and disease.