Mutation in Sos1 dominantly enhances a weak allele of the EGFR, demonstrating a requirement for sos1 in EGFR signaling and development

Abstract

We have investigated the role of the mammalian Son of sevenless 1 (Sos1) protein in growth factor signaling in vivo by generating mice and cell lines that lacked the Sos1 protein. Homozygous null embryos were smaller than normal, died mid-gestation with cardiovascular and yolk sac defects, and their fibroblasts showed reduced mitogen-activated protein kinase activation in response to epidermal growth factor (EGF). An intercross of mice mutant for Sos1 and the EGF receptor (EGFR) demonstrated that a heterozygous mutation in Sos1 dominantly enhanced the phenotype of a weak allele of the EGFR allele (wa-2). These animals had distinctive eye defects that closely resembled those seen in mice that were null for the EGFR or its ligand, TGFα. Our findings provide the first demonstration of a functional requirement for Sos1 in growth factor signaling in vivo. They also show that the genetic test of enhancement of weak receptor allele by heterozygous mutation in one component represents a powerful tool for analyzing the ras pathway in mammals.