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First published online January 13, 2009
doi: 10.1242/10.1242/dev.021295

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Embryonic hair follicle fate change by augmented β-catenin through Shh and Bmp signaling

¹ Center for Animal Resources and Development (CARD), Kumamoto University, Kumamoto 860-0811, Japan.
² Global COE `Cell Fate Regulation Research and Education Unit', Kumamoto University, Kumamoto 860-0811, Japan.
³ Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
⁴ Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
⁵ Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁶ Department of Molecular Biochemistry, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan.
⁷ Cancer and Developmental Biology Laboratory, National Cancer Institute-Frederick, NIH Frederick, MD 21702, USA.
⁸ Department of Cancer Biology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
⁹ Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.

View larger version (46K): [in this window] [in a new window]   Fig. 1. Switching of embryonic epidermal keratinocytes to HF fate in K5-Cre Catnb(ex3)fl/+ mutant skin. (A,B) Gross appearance of control and of K5-Cre Catnb(ex3)fl/+ mutant skin at E18.5. (C,D) Histology of control and of K5-Cre Catnb(ex3)fl/+ mutant skin at E18.5. (E-H) Epidermal differentiation marker expression: K1 (brown) and loricrin (green) at E18.5. (I,J) Immunostaining with AE13 antibody to detect hair shaft keratins (red) at E18.5. (K,L) Histological alteration of the K5-Cre Catnb(ex3)fl/+ mutant dermis compared with control, showing the dermal condensate throughout the upper dermis. Arrowheads in K indicate dermal condensate. (M,N) Bmp2 expression is broadly induced in K5-Cre Catnb(ex3)fl/+ mutant epidermis at E16.5. (O,P) Bmp4 expression is ectopically detected in the mutant epidermis at E15.0. (Q,R) The pSMAD level is prominently increased in the mutant epidermis and dermis compared with the control. (S,T) Shh expression is broadly detected in the mutant epidermis at E18.5. (U-Z) The dermal condensate markers noggin, Ptch1 and Pdgfra are expressed throughout the upper dermis in K5-Cre Catnb(ex3)fl/+ skin at E16.5. Dashed lines indicate the dermal-epithelial border. Scale bars: 1 mm for A,B; 50 µm for C-J,M-R; 25 µm for K,L,S-Z.

View larger version (89K): [in this window] [in a new window]   Fig. 2. The loss of Bmp signaling in the epidermis restores the K5-Cre Catnb(ex3)fl/+ mutant HF-like differentiation. (A-C) Histological analysis of control, K5-Cre Catnb(ex3)fl/+ and double mutant skin at E18.5. (D-L) The restoration of loricrin (green) and K1 (red) expression, and the suppression of expression of hair shaft keratins recognized by AE13 antibody (red), in double mutant skin at E18.5. (M-R) In situ hybridization for Msx2 and Lef1 expression at E16.5. (S-U) Upon induction, expression of hair placode marker gene Bmp2 remained in the K5-Cre Catnb(ex3)fl/+ BmprIAfl/fl mutant epidermis. Dashed lines indicate the dermal-epithelial border. Scale bars: 50 µm for A-L; 100 µm for M-U.

View larger version (76K): [in this window] [in a new window]   Fig. 3. The involvement of Shh signaling as a crucial downstream effector of β-catenin signaling for the excessive HF induction. (A,B) Suppression of excessive HF induction in the double conditional mutant K5-Cre Catnb(ex3)fl/+Shhfl/- at E16.5. (C-J) Suppression of induced Bmp2, Wnt10b and Dkk1 expression, and of AE13 antibody staining (red), in the double mutant skin at E16.5. (K,L) Cell proliferation analysis using Ki67 antibody at E18.5. Cell proliferation is increased in K5-Cre Catnb(ex3)fl/+ mutant (K) and is suppressed in K5-Cre Cantb(ex3)fl/+Shhfl/- double mutant (L) epidermis. Dashed lines indicate the dermal-epithelial border. Scale bars: 50 µm for A-L.

View larger version (28K): [in this window] [in a new window]   Fig. 4. A possible regulatory mechanism between Shh and Bmp signaling that underlies Wnt/β-catenin signaling pathway. (A-C) The intensity of pSMAD staining in K5-Cre Cantb(ex3)fl/+ is suppressed both in the epidermis and the mesenchyme of K5-Cre Cantb(ex3)fl/+Shhfl/- skin at E16.5 (C, brackets). Such intense pSMAD staining remains in early-induced HFs (outside of the brackets). (D) Activation of the Bmp2 promoter (Bmp2 p-Luc) by introducing the activated Gli2 expression vector; the activation is diminished by deleting the two putative GLI-binding sites (yellow boxes; del Bmp2 p-Luc). (E-G) Shh protein expression is increased and expanded in K5-Cre Cantb(ex3)fl/+BmprIAfl/fl mutant epidermis at E16.5. (H) Schematic of the growth factor network regulating HF fate change. Scale bars: 50 µm for A-C,E-G.

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