title: Embryonic hair follicle fate change by augmented beta-catenin through Shh and Bmp signaling.
abstract: beta-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 beta-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/+Shhfl/- (with additional mutation of Shh signaling) or K5-Cre Catnb(ex3)fl/+BmprIAfl/fl (with additional mutation of Bmp signaling). These results demonstrate that Wnt/beta-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 beta-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/+BmprIAfl/fl mice. These results indicate the presence of growth factor signal cross-talk involving beta-catenin signaling, which regulates the HF fate.
authors.affiliation: Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Mylah
authors.initials: M
authors.lastname: Villacorte
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Mihara
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.forename: Tadasuke
authors.initials: T
authors.lastname: Tsukiyama
authors.forename: Terry P
authors.initials: TP
authors.lastname: Yamaguchi
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D018859:Hair Follicle / Q000166:cytology* / Q000196:embryology / Q000502:physiology; D053823:Hedgehog Proteins / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D053564:Keratins, Hair-Specific / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D053823:Hedgehog Proteins; D053564:Keratins, Hair-Specific; C465570:Shh protein, mouse; D051176:beta Catenin