β-Catenin and Hedgehog Signal Strength Can Specify Number and Location of Hair Follicles in Adult Epidermis without Recruitment of Bulge Stem Cells

Abstract

Using K14deltaNbeta-cateninER transgenic mice, we show that short-term, low-level beta-catenin activation stimulates de novo hair follicle formation from sebaceous glands and interfollicular epidermis, while only sustained, high-level activation induces new follicles from preexisting follicles. The Hedgehog pathway is upregulated by beta-catenin activation, and inhibition of Hedgehog signaling converts the low beta-catenin phenotype to wild-type epidermis and the high phenotype to low. beta-catenin-induced follicles contain clonogenic keratinocytes that express bulge markers; the follicles induce dermal papillae and provide a niche for melanocytes, and they undergo 4OHT-dependent cycles of growth and regression. New follicles induced in interfollicular epidermis are derived from that cellular compartment and not through bulge stem cell migration or division. These results demonstrate the remarkable capacity of adult epidermis to be reprogrammed by titrating beta-catenin and Hedgehog signal strength and establish that cells from interfollicular epidermis can acquire certain characteristics of bulge stem cells.

Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin

“…GSK3b acts in the Wnt pathway but also regulates Hedgehog signaling, including the Gli1-target gene Snail (Zhou et al, 2004;Bachelder et al, 2005;Yook et al, 2005;Price, 2006). Wnt and Shh signals play distinct roles in the development of hair follicles in the skin (Alonso and Fuchs, 2003;Silva-Vargas et al, 2005;Brembeck et al, 2006). Wnt signals initiate hair bud and follicle formation, whereas Shh signals potentiate the Wnt effects and are required for the subsequent proliferation/migration of bud or follicle cells.…”

“…Loss of E-cad during tumor progression could likewise promote Wnt signaling (Nelson and Nusse, 2004;Bienz, 2005). However, E-cad loss-of-function in tumor cells is not often associated with increased b-catenin signaling and specific contexts in which the cadherin-bound pool of b-catenin is released for signaling remain poorly understood (van de Wetering et al, 2001;Gottardi and Gumbiner, 2004;Nelson and Nusse, 2004;Gumbiner, 2005).…”

Development and Homeostasis of the Skin Epidermis

“…In addition, Shh is expressed in the mesenchymal part of the hair (Oro and Higgins 2003), suggesting that Shh signaling plays a role in the epithelial-mesenchymal interaction regulating hair cycle. Ectopic administration of Shh or Shh agonists stimulates the proportion of hair in its growing stage (Sato et al 1999;Paladini et al 2005), and administration of Shh inhibitor blocks anagen progression (Wang et al 2000;Silva-Vargas et al 2005), showing that Shh exhibits a role in mediating anagen progression during the hair cycle. Gli2-deficient mice present an arrest in HF development similar to Shhnull mice, which is rescued by overexpression of a constitutively active but not wild-type form of Gli2 in the epidermis , showing that Gli2 expression in the epidermis is essential to mediate Shh signaling during HF morphogenesis.…”

SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity

“…After four washes in phosphate-buffered saline, the cells were incubated with secondary antibodies for 45 min at room temperature, washed three times in phosphate-buffered saline and mounted using Prolong Gold antifade reagent (Molecular Probes-Invitrogen). Conventional fixed and paraffin-embedded sections of human tumours or tumours generated by SNAIL-HA cells in immunodeficient scid mice (Pa´lmer et al, 2004) were prepared and immunolabelled as described elsewhere (Silva-Vargas et al, 2005). Briefly, antigens were retrieved by microwaving in 10 mM citrate buffer (pH 6.0) for 10 min and permeabilized with 0.2% Triton X-100 (Sigma).…”