As inherent components of the EGFR signaling system, the EGFR ligands are expressed in several tissues and elicit manifold actions during development and in adult mammals. It is therefore initially surprising that HBEGF is the only ligand whose absence results in postnatal lethality—due to malformed heart valves, hypertrophic cardiomyocytes, and hypoplastic lungs (Iwamoto et al., 2003; Jackson et al., 2003)—while mice lacking AREG (Luetteke et al., 1999), BTC (Jackson et al., 2003), EGF (Luetteke et al., 1999), EREG (Mann et al., 1993; Lee et al., 2004; Shirasawa et al., 2004), TGFA (Luetteke et al., 1993), and even triple null mice deficient for AREG, EGF, and TGFA (Luetteke et al., 1999) are viable. These observations clearly point to a high degree of functional redundancy compensation within the family of EGFR ligands. Nevertheless, many of these mouse lines show specific phenotypes, and careful examination under challenge situations further disclosed homeostasis defects in apparently normal tissues. For example, while only mammary gland defects were initially reported in AREG knockout mice, further studies additionally revealed reduced tibial trabecular bone (Qin et al., 2005) and impaired liver regeneration after partial liver resection (Berasain et al., 2005). Interestingly, many phenotypes observed in mice lacking individual EGFR ligands, such as the hair follicle and eyelid closure defects in TGFA knockout mice (Luetteke et al., 1993; Mann et al., 1993), or the heart valve defects and the lung immaturity in HBEGF-deficient animals (Iwamoto et al., 2003; Jackson et al., 2003), are also observed in mice lacking the EGFR (Miettinen et al., 1995; Sibilia and Wagner, 1995; Threadgill et al., 1995; Chen et al., 2000).
Additional evidence for specific actions of these proteins also comes from in vitro studies and from the phenotype of transgenic animals overexpressing individual EGFR ligands (see below). Often, as for BTC (Schneider et al., 2005) and EGF (Chan and Wong, 2000; Wong et al., 2000), overexpressing the EGFR ligand results in profuse, complex phenotypes which are in sharp contrast to the inconspicuousness of mice lacking the respective ligand (Luetteke et al., 1999; Jackson et al., 2003), rendering this approach more suitable for the study of potential actions of these molecules. Transgenic mice overexpressing EGFR ligands have also been very informative concerning the role of these molecules in tumorigenesis and other diseases. The most prominent and classical example is the large array of neoplastic lesions observed in mice overexpressing TGFA (Jhappan et al., 1990; Matsui et al., 1990; Sandgren et al., 1990), including hepatocarcinogenesis, pancreatic metaplasia, dysplasia of the coagulation gland epithelium, and mammary adenocarcinoma. Since then, the EGFR ligands have been implicated in the pathogenesis of a large number of disorders. These include a role for EREG in mediating breast cancer metastasis to the lung (Minn et al., 2005), isolated recessive renal hypomagnesemia as a consequence of impaired basolateral sorting of EGF (Groenestege et al., 2007), and increased TGFA expression as the causing agent of the rare gastric disorder Ménétrier disease (Dempsey et al., 1992; Takagi et al., 1992; Coffey et al., 2007), just to mention a few cases.