TY - JOUR T1 - Fine-tuning of Epithelial EGFR signals Supports Coordinated Mammary Gland Development JF - bioRxiv DO - 10.1101/2020.09.10.291872 SP - 2020.09.10.291872 AU - Alexandr Samocha AU - Hanna M. Doh AU - Vaishnavi Sitarama AU - Quy H. Nguyen AU - Oghenekevwe Gbenedio AU - Joshua D. Rudolf AU - Walter L. Eckalbar AU - Andrea J. Barczak AU - Yi Miao AU - K. Christopher Garcia AU - Devon Lawson AU - Zena Werb AU - Kai Kessenbrock AU - Philippe Depeille AU - Jeroen P. Roose Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/09/10/2020.09.10.291872.abstract N2 - During puberty, robust morphogenesis occurs in the mammary gland; stem- and progenitor-cells develop into mature basal- and luminal-cells to form the ductal tree. The receptor signals that govern this process in mammary epithelial cells (MECs) are incompletely understood. The EGFR has been implicated and here we focused on EGFR’s downstream pathway component Rasgrp1. We find that Rasgrp1 dampens EGF-triggered signals in MECs. Biochemically and in vitro, Rasgrp1 perturbation results in increased EGFR-Ras-PI3K-AKT and mTORC1-S6 kinase signals, increased EGF-induced proliferation, and aberrant branching-capacity in 3D cultures. However, in vivo, Rasgrp1 perturbation results in delayed ductal tree maturation with shortened branches and reduced cellularity. Rasgrp1-deficient MEC organoids revealed lower frequencies of basal cells, the compartment that incorporates stem cells. Molecularly, EGF effectively counteracts Wnt signal-driven stem cell gene signature in organoids. Collectively, these studies demonstrate the need for fine-tuning of EGFR signals to properly instruct mammary epithelium during puberty.Competing Interest StatementJeroen Roose is a co-founder and scientific advisor of Seal Biosciences, Inc. and on the scientific advisory committee for the Mark Foundation for Cancer Research. ER -