[PDF][PDF] Transgenic mouse lines help decipher the roles of EGFR ligands in the skin

M Dahlhoff, MR Schneider - Experimental Dermatology, 2016 - researchgate.net
M Dahlhoff, MR Schneider
Experimental Dermatology, 2016researchgate.net
The epidermal growth factor receptor (EGFR/ERBB1), a prototypical tyrosine kinase receptor
belonging to the ERBB family (ERBB1-ERBB4), has numerous critical roles during
development, growth and tissue homeostasis. Its essentially pro-proliferative actions are
frequently exploited by tumor cells, and blocking the activity of the EGFR and of the related
ERBB receptors with monoclonal antibodies or kinase inhibitors represents an important
strategy for the therapy of various cancer types (1). Canonical activation of the EGFR …
The epidermal growth factor receptor (EGFR/ERBB1), a prototypical tyrosine kinase receptor belonging to the ERBB family (ERBB1-ERBB4), has numerous critical roles during development, growth and tissue homeostasis. Its essentially pro-proliferative actions are frequently exploited by tumor cells, and blocking the activity of the EGFR and of the related ERBB receptors with monoclonal antibodies or kinase inhibitors represents an important strategy for the therapy of various cancer types (1). Canonical activation of the EGFR involves binding by a ligand, induction of receptor homo-or heterodimers, phosphorylation of the intra-cellular kinase and the initiation of diverse signaling pathways. EGFR ligands include seven different peptides: EGF, transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), amphiregulin (AREG), betacellulin (BTC), epiregulin (EREG) and epigen (EPGN). These ligands, initially synthesized as membrane-bound proteins containing an EGF-like domain in the extracellular region (Fig. 1), may be released by specific proteases to release the mature, soluble growth factor. The diversity of ligands, their differential expression patterns and their ability to initiate distinct signaling pathways collectively represent a major regulator and determinant of the actions elicited by the EGFR (2). However, many details of the functions played by the EGFR ligands and the molecular basis of their functional diversity remain poorly understood.
Over the last 20 years, overexpressing EGFR ligands in transgenic mice provided important insights into their role in skin biology and pathology. The first EGFR ligand to be studied in detail with this strategy was TGFA, whose overexpression employing different ubiquitous or tissue-specific promoters in the early 1990s highlighted its ability to robustly induce epidermal hyperproliferation and to increase the susceptibility to skin tumorigenesis (Table 1). A few years later, it was reported that AREG induced epidermal hyperplasia with many similarities to psoriatic lesions when overexpressed in basal (S1) or suprabasal (S2) keratinocytes by employing the keratin 14 or involucrin promoters, respectively. However, more in-depth studies were precluded by the high mortality and the breeding inability of these mice. In this issue of Experimental Dermatology, Li et al.(3) report novel mouse lines overexpressing human AREG under the control of the bovine keratin 5 promoter (K5-AREG). While these mice present a similar phenotype as the founders produced previously by Cook and colleagues (see below), the novel mouse lines are fertile and produce transgenic offspring at the expected Mendelian ratios. This important advantage enables researchers to use these mice for further studies such as the induction of skin inflammation or tumorigenesis. K5-AREG mice showed a greasy hair coat, prolonged and curved nails, significantly increased thickness of the back skin and thickened erythematous tail skin with acanthosis. K5-AREG mice also developed an increased tail diameter and more prominent plate markings, and some of the transgenic animals additionally developed scaling and crusting of tail skin. Furthermore, the epidermal hyperplasia is associated with lymphocytic infiltration and increased numbers of CD4+ T-cells. As the authors discuss, while these phenotypical changes observed in K5-AREG mice have some similarities to human psoriasis, the disparities seem to overweigh them. Important differences include non-coinciding inflammation-associated signaling pathways, and the fact that the sebaceous gland enlargement observed in K5-AREG mice is exactly the opposite of what is …
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