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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.

^* Author for correspondence (e-mail: gensan{at}gpo.kumamoto-u.ac.jp)

Accepted 17 November 2008

SUMMARY

β-catenin signaling is one of the key factors regulating the fate of hair follicles (HFs). To elucidate the regulatory mechanism of embryonic HF fate determination during epidermal development/differentiation, we analyzed conditional mutant mice with keratinocytes expressing constitutively active β-catenin (K5-Cre Catnb^(ex3)fl/+). The mutant mice developed scaly skin with a thickened epidermis and showed impaired epidermal stratification. The hair shaft keratins were broadly expressed in the epidermis but there was no expression of the terminal differentiation markers K1 and loricrin. Hair placode markers (Bmp2 and Shh) and follicular dermal condensate markers (noggin, patched 1 and Pdgfra) were expressed throughout the epidermis and the upper dermis, respectively. These results indicate that the embryonic epidermal keratinocytes have switched extensively to the HF fate. A series of genetic studies demonstrated that the epidermal switching to HF fate was suppressed by introducing the conditional mutation K5-Cre Catnb^(ex3)fl/+Shh^fl/- (with additional mutation of Shh signaling) or K5-Cre Catnb^(ex3)fl/+BmprIA^fl/fl (with additional mutation of Bmp signaling). These results demonstrate that Wnt/β-catenin signaling relayed through Shh and Bmp signals is the principal regulatory mechanism underlying the HF cell fate change. Assessment of Bmp2 promoter activities suggested a putative regulation by β-catenin signaling relayed by Shh signaling towards Bmp2. We also found that Shh protein expression was increased and expanded in the epidermis of K5-Cre Catnb^(ex3)fl/+BmprIA^fl/fl mice. These results indicate the presence of growth factor signal cross-talk involving β-catenin signaling, which regulates the HF fate.

Key words: Skin, Hair follicle (HF), Wnt, β-catenin, Bmp, Shh, Cell fate

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