Epidermal Wnt controls hair follicle induction by orchestrating dynamic signaling crosstalk between the epidermis and dermis - PubMed (original) (raw)

Epidermal Wnt controls hair follicle induction by orchestrating dynamic signaling crosstalk between the epidermis and dermis

Jiang Fu et al. J Invest Dermatol. 2013 Apr.

Abstract

A signal first arising in the dermis to initiate the development of hair follicles has been described for many decades. Wnt is the earliest signal known to be intimately involved in hair follicle induction. However, it is not clear whether the inductive signal of Wnt arises intradermally or intraepidermally. Whether Wnt acts as the first dermal signal to initiate hair follicle development also remains unclear. Here we report that Wnt production mediated by Gpr177, the mouse Wls ortholog, is essential for hair follicle induction. Gpr177, encoding a multipass transmembrane protein, regulates Wnt sorting and secretion. Cell type-specific abrogation of the signal reveals that only epidermal, but not dermal, production of Wnt is required. An intraepidermal Wnt signal is necessary and sufficient for hair follicle initiation. However, the subsequent development depends on reciprocal signaling crosstalk of epidermal and dermal cells. Wnt signals within the epidermis and dermis and crossing between the epidermis and dermis have distinct roles and specific functions in skin development. This study not only defines the cell type responsible for Wnt production, but also reveals a highly dynamic regulation of Wnt signaling at different steps of hair follicle morphogenesis. Our findings uncover a mechanism underlying hair follicle development orchestrated by the Wnt pathway.

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Figures

Fig. 1

Fig. 1

Gpr177 is expressed in hair follicle development. Immunostaining of the E11.5 (a) and E13.5 (b) skins shows the expression of Gpr177 in the epithelium and underlying mesenchyme. A restricted elevation is found in the epidermal basal cells and hair follicular cells at E15.5 (c) and E17.5 (d), respectively. The inset shows non-uniform expression of Gpr177 in the hair follicle (d). Double labeling of Gpr177 (e-l) with AE3, a marker for the entire epidermis (e, g, i, k), or K14, a marker for the epidermal basal layer (f, h, j, l), identifies the Gpr177-expressing cells at E14.5 (e-f, i-j) and E17.5 (g-h, k-l). Scale bars, 50 μm (a-l).

Fig. 2

Fig. 2

Epidermal deletion of Gpr177 abrogates the induction of hair follicles. β-gal staining of the E13.5 (a) and E14.5 (b) K5-Cre; R26R embryos analyzes the effectiveness of Cre recombination in the epidermis and hair placode. Sections of the control and Gpr177K5 embryos were analyzed by co-immunostaining of Gpr177 and K14 (c-d) and hematoxylin/eosin staining (e-h) at E14.5 (c-f) and E17.5 (g-h). Whole mount in situ hybridization of the control (i, k, m, o) and Gpr177K5 (j, l, n, p) embryos reveals the expression of Edar (i-j), Bmp2 (k-l), Bmp4 (m-n) and Shh (o-p) at E14.5. Control genotype: Gpr177Fx/Fx or K5-Cre; Gpr177Fx/+. Scale bars, 50 μm (a-h); 200 μm (i-p).

Fig. 3

Fig. 3

Wnt expression and signaling are affected by the epidermal deletion of Gpr177. In situ hybridization in sections shows the expression of Wnt genes in the E14.5 control (a-k) and Gpr177K5 (a’-k’) skins. Sections of control (l-o) and Gpr177K5 (l’-o’) skins examine the signaling activity of Wnt by immunostaining of an activated form of β-catenin (ABC) and β-gal staining of the Axin2lacZ allele at E13.5 (n, n’), E14.5 (l, l’, o, o’) and E17.5 (m, m’). In situ hybridization analyzes the expression of Wnt downstream targets, Lef1 (p, p’) and Dkk4 (q, q’) in the E14.5 control (p-q) and Gpr177K5 (p’-q’) skins. Control genotype: Gpr177Fx/Fx or K5-Cre; Gpr177Fx/+. Scale bars, 50 μm (a-q, a’-q’).

Fig. 4

Fig. 4

Epidermal stimulation of β-catenin alleviates the hair follicle defects of Gpr177K5. Sections of the control, Gpr177K5 and Gpr177K5; sβcatK5 were analyzed by H&E staining (a-c), immunostaining of Gpr177 (d-f), ABC (g-i) and K17 (p-r), in situ hybridization of Edar (j-l) and Shh (m-o), and double labeling of CD133 and AE3 (s-u) or Sox2 and AE3 (v-x) at E14.5 and E15.5. Arrowhead indicates the dermal activation of β-catenin in the control (g), but not in the Gpr177K5 and Gpr177K5; sβcatK5 mutants (h-i). Asterisks indicate the dermal papilla markers, CD133 and Sox2, are detected in the control (s, v), but absent in the Gpr177K5; sβcatK5 mutants (q-r, t-u). Control genotype: Gpr177Fx/Fx or K5-Cre. Scale bars, 50 μm (a-x).

Fig. 5

Fig. 5

The Gpr177-mediated regulation of Wnt in the dermis is dispensable for hair follicle initiation. β-gal staining of the E14.5 control and Gpr177Dermo1 skins carrying R26R shows Cre effectiveness (a-b). Sections are analyzed by co-labeling of Gpr177 and K14 (c-f) or CD133 and AE3 (q-r), H&E (g-h), immunostaining of Cadherin (i-l) and ABC (s-t) and in situ hybridization of Edar (m-n) and Shh (o-p), and β-gal staining of the Axin2lacZ allele (u-x) at E13.5, E14.5 and E15.5. (y) Graph indicates quantitative analysis for the placode region and the expression domain for ABC, Edar and Shh. Control genotype: Gpr177Fx/Fx or Dermo1-Cre; Gpr177Fx/+. Scale bars, 50 μm (a-x). (z) Model for epidermal Wnt in orchestrating signaling interaction between the epidermis and dermis during hair follicle development.

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