Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor

Abstract

Since the discovery that epidermal growth factor (EGF) can accelerate opening of the eyelids, the EGF receptor (EGF-R) has been extensively studied and is now considered to be a prototype tyrosine kinase receptor. Binding of EGF or of transforming growth factor-alpha (TGF-alpha) or other related factors activates the receptor and induces cell proliferation and differentiation. Although it is not found on haematopoietic cells, the EGF-R is widely expressed in mammals and has been implicated in various stages of embryonic development. Here we investigate the developmental and physiological roles of this receptor and its ligands by inactivating the gene encoding EGF-R. We find that EGF-R-/- mice survive for up to 8 days after birth and suffer from impaired epithelial development in several organs, including skin, lung and gastrointestinal tract.

Evidence that MIG-6 is a tumor-suppressor gene

“…MIG-6 is a scaffolding protein involved in receptor signal transduction. The expression of MIG-6 is induced by EGF, whose signaling plays an important role in normal lung development (Miettinen et al, 1995(Miettinen et al, , 1997. Like many other tyrosine kinase receptors, EGF receptor signaling needs to be attenuated after activation; constitutive activation is deleterious to normal lung epithelial cells and can lead to carcinogenesis (Zochbauer-Muller et al, 2002;Paez et al, 2004;Stephens et al, 2004).…”

Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning

“…These include mutations in the TGF␣ (Luetteke et al, 1993), EFG receptor (Miettinen et al, 1995), activin/inhibin ␤B (Vassalli et al, 1994), and lipgap-Gates (IgGa) genes (Juriloff et al, 1996(Juriloff et al, , 2000. Of note, these mutant embryos could form protruding ridges at E13.5 and the "open-eyelids-at-birth" syndrome is primarily caused by a failure of eyelid fusion.…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Wide variation in the phenotypes of EGFR-deficient mice in different genetic backgrounds highlights the amount of redundancy and regulation within this system. EGFR-deficient mice die from preimplantation to 3 weeks postnatally depending on genetic background and show defects in cell proliferation, differentiation and migration in a wide range of tissues including skin, central nervous system, intestines, lung, liver, kidneys, placenta, palate and facies [113][114][115][116]. Strain-independent neurodegeneration within the frontal cortex, olfactory bulbs, and thalamus occurs postnatally in EGFR-deficient mice as well [117,118].…”