Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure.

Abstract

Epidermal growth factor receptor (EGFR) is a key regulator of keratinocyte biology. However, the physiological role of EGFR in vivo has not been well established. To analyze the role of EGFR in skin, we have generated transgenic mice expressing an EGFR dominant negative mutant in the basal layer of epidermis and outer root sheath of hair follicles. Mice expressing the mutant receptor display short and waved pelage hair and curly whiskers during the first weeks of age, but subsequently pelage and vibrissa hairs become progressively sparser and atrophic. Eventually, most mice present severe alopecia. Histological examination of the skin of transgenic mice shows striking alterations in the development of hair follicles, which fail to enter into catagen stage. These alterations eventually lead to necrosis and disappearance of the follicles, accompanied by strong infiltration of the skin with inflammatory elements. The interfollicular epidermis of these mice shows marked hyperplasia, expression of hyperproliferation‐associated keratin K6 and increased 5‐bromo‐2‐deoxyuridine incorporation. EGFR function was inhibited in transgenic skin keratinocytes, since in vivo and in vitro autophosphorylation of EGFR was almost completely abolished on EGF stimulation. These results implicate EGFR in the control of hair cycle progression, and provide new information about its role in epidermal growth and differentiation.

Targeted Disruption of the Protein Kinase SGK3/CISK Impairs Postnatal Hair Follicle Development

“…It also should be noted that in addition to proliferation, SGK3 might influence cell migration and differentiation. It is notable that although no member of the SGK/Akt family has previously been identified as a primary mediator of hair follicle development, growth factor receptors that signal through PI3K have been strongly implicated in follicle development (Luetteke et al, 1994;Murillas et al, 1995;Sibilia and Wagner, 1995;Threadgill et al, 1995). Together, our present data suggest that SGK3 may play a role in linking PI3K signaling (possibly through EGFR-dependent activation of this pathway) to the regulation of both forkhead (traditional pathway) and ␤-catenin (alternate pathway).…”

“…This initial abnormality persisted for at least 4 wk ( Figure 2B); however, as the Sgk3 KO mice increased in age, the hair became increasingly thick ( Figure 2C). At all ages, Sgk3 KO mice displayed wavy coat fur and curly vibrissae that resembled those of mice with spontaneously or engineered mutations in the EGF/TGF-␣ and ␤-catenin signaling pathways (see below) (Luetteke et al, 1993(Luetteke et al, , 1994Mann et al, 1993;Murillas et al, 1995;Sibilia and Wagner, 1995;Threadgill et al, 1995;Hansen et al, 1997;Gat et al, 1998;DasGupta and Fuchs, 1999;Fuchs et al, 2001;Huelsken et al, 2001;Andl et al, 2002).…”

“…Mutations in both growth factor-regulated PI3K-dependent pathways (Luetteke et al, 1993(Luetteke et al, , 1994Mann et al, 1993;Murillas et al, 1995;Sibilia and Wagner, 1995;Threadgill et al, 1995;Hansen et al, 1997), and in the Wnt-␤-catenin/Lef1 (Gat et al, 1998;DasGupta and Fuchs, 1999;Fuchs et al, 2001;Huelsken et al, 2001;Andl et al, 2002) pathway have been associated with hair development abnormalities that resemble the SGK3 KO in many respects (see Discussion and below). Growth factors have well characterized inhibitory effects on forkhead-mediated gene transcription (Jackson et al, 2000), and recent evidence has suggested that EGF in par- ticular also may regulate ␤-catenin activities (Muller et al, 2002;Lu et al, 2003).…”

Cyclin D2 Overexpression in Transgenic Mice Induces Thymic and Epidermal Hyperplasia whereas Cyclin D3 Expression Results Only in Epidermal Hyperplasia

“…As reported, this fragment drives expression of a reporter gene in basal cells of squamous stratified epithelia, where K5 is normally expressed. 32,33 All of the transgenic mice were generated in the C57BL/6xSJL genetic background. Three mice with cyclin D3-positive and five mice with cyclin D2-positive integration were identified by PCR analysis ( Figure 1B).…”

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

“…Two pathways that have an essential role in these cell fate decisions include EGF and KGF (FGF7 -Mouse Genome Informatics) (Beer et al, 2000;du Cros, 1993;Peus and Pittelkow, 1996;Schneider et al, 2008, Guo et al, 1996. Disruption or blocking of the EGF receptor (EGFR) in several mouse models results in abnormalities occurring late on in follicle development and during the adult hair follicle cycle, leading to the hypothesis that EGF signalling has an important positive influence on follicle development and growth (Miettinen et al, 1995;Murillas et al, 1995). EGFR also has several other activating ligands, including transforming growth factor-α (TGFα), heparin-binding EGF-like growth factor (HBEGF), amphiregulin (AR, AREG -Mouse Genome Informatics), betacellulin (BTC), epiregulin (EPR, EREG -Mouse Genome Informatics) and epigen (EPGN).…”