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First published online 14 May 2008
doi: 10.1242/dev.017459
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1 Departments of Dermatology and Cell and Developmental Biology, University of
Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
2 Department of Dermatology, University of Michigan, Ann Arbor, MI 48109,
USA.
3 Department of Dermatology, University of Pennsylvania School of Medicine,
Philadelphia, PA 19104, USA.
4 Bioinformatics Core, University of Pennsylvania, Philadelphia, PA 19104,
USA.
5 Department of Histology, Microbiology and Medical Biotechnologies, Section of
Histology and Embryology, University of Padua, 35121 Padua, Italy.
6 Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse
10, 13092 Berlin, Germany.
7 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario,
M5G 1X5, Canada.
8 Department of Pharmacology, Graduate School of Medicine, Kyoto University,
Yoshida-Konoé-cho, Sakyo, Kyoto 606-8501, Japan.
* Author for correspondence (e-mail: millars{at}mail.med.upenn.edu)
Accepted 24 April 2008
β-Catenin signaling is required for hair follicle development, but it is unknown whether its activation is sufficient to globally program embryonic epidermis to hair follicle fate. To address this, we mutated endogenous epithelial β-catenin to a dominant-active form in vivo. Hair follicle placodes were expanded and induced prematurely in activated β-catenin mutant embryos, but failed to invaginate or form multilayered structures. Eventually, the entire epidermis adopted hair follicle fate, broadly expressing hair shaft keratins in place of epidermal stratification proteins. Mutant embryonic skin was precociously innervated, and displayed prenatal pigmentation, a phenomenon never observed in wild-type controls. Thus, β-catenin signaling programs the epidermis towards placode and hair shaft fate at the expense of epidermal differentiation, and activates signals directing pigmentation and innervation. In transcript profiling experiments, we identified elevated expression of Sp5, a direct β-catenin target and transcriptional repressor. We show that Sp5 normally localizes to hair follicle placodes and can suppress epidermal differentiation gene expression. We identified the pigmentation regulators Foxn1, Adamts20 and Kitl, and the neural guidance genes Sema4c, Sema3c, Unc5b and Unc5c, as potential mediators of the effects of β-catenin signaling on pigmentation and innervation. Our data provide evidence for a new paradigm in which, in addition to promoting hair follicle placode and hair shaft fate, β-catenin signaling actively suppresses epidermal differentiation and directs pigmentation and nerve fiber growth. Controlled downregulation of β-catenin signaling is required for normal placode patterning within embryonic ectoderm, hair follicle downgrowth, and adoption of the full range of follicular fates.
Key words: Epidermis, Hair follicle, Mouse embryo, β-catenin, Wnt
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