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

Abstract

A key initial event in hair follicle morphogenesis is the localised thickening of the skin epithelium to form a placode, partitioning future hair follicle epithelium from interfollicular epidermis. Although many developmental signalling pathways are implicated in follicle morphogenesis, the role of epidermal growth factor (EGF) and keratinocyte growth factor (KGF, also known as FGF7) receptors are not defined. EGF receptor (EGFR) ligands have previously been shown to inhibit developing hair follicles; however, the underlying mechanisms have not been characterised. Here we show that receptors for EGF and KGF undergo marked downregulation in hair follicle placodes from multiple body sites, whereas the expression of endogenous ligands persist throughout hair follicle initiation. Using embryonic skin organ culture, we show that when skin from the sites of primary pelage and whisker follicle development is exposed to increased levels of two ectopic EGFR ligands (HBEGF and amphiregulin) and the FGFR2(IIIb) receptor ligand KGF, follicle formation is inhibited in a time-and dose-dependent manner. We then used downstream molecular markers and microarray profiling to provide evidence that, in response to KGF and EGF signalling, epidermal differentiation is promoted at the expense of hair follicle fate. We propose that hair follicle initiation in placodes requires downregulation of the two pathways in question, both of which are crucial for the ongoing development of the interfollicular epidermis. We have also uncovered a previously unrecognised role for KGF signalling in the formation of hair follicles in the mouse.

Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles

“…Fgf receptor 2b (Fgfr2b) is expressed in the epithelium of developing skin, and deletion of Fgfr2b resulted in fewer and retarded hair follicle formation (Petiot et al 2003;Richardson et al 2009). In addition, deletion of both Fgfr1 and Fgfr2 in keratinocytes resulted in progressive loss of hair follicles in adult mice .…”

“…In addition, deletion of both Fgfr1 and Fgfr2 in keratinocytes resulted in progressive loss of hair follicles in adult mice . Fgf10 is required for whisker formation, whereas Fgf7 is suggested to inhibit hair follicle induction (Ohuchi et al 2003;Richardson et al 2009). …”

Kil Foli̇külü Geli̇şi̇mi̇ Üzeri̇ne Etki̇li̇ Genler

“…Besides it is thought that Fibroblast Growth Factor Receptor (FGFR1) gene may be one of initiator factors of the hair morphogenesis (6). In the formation of placode, genes of Keratinocyte Growth Factor (KGF also known as FGF7) and Epidermal Growth Factor (EGF) also have functions as inhibitory (28,33) (Figure 3) (Table 1). Hair follicle begins to organogenesis when placode have enough amount.…”

Progress in Relevant Growth Factors Promoting the Growth of Hair Follicle

“…It was also indicated that KGF had marked effects on the epithelialization and healing of wounds (Macleod and Havran, 2011). Richardson et al (2009) proved that receptors for EGF and KGF underwent marked downregulation in hair follicle placodes from multiple body sites, whereas the expression of endogenous ligands persisted throughout hair follicle initiation. When skin from the sites of primary pelage and whisker follicle development was exposed to increase levels of two ectopic EGFR ligands and the FGFR2 (IIIb) receptor ligand KGF, follicle formation was inhibited in a time-and dose-dependent manner.…”