Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice

Abstract

Wnts have key roles in many developmental processes, including hair follicle growth and differentiation. Stabilization of ␤-catenin is essential in the canonical Wnt signaling pathway. We developed transgenic mice expressing a regulated form of ␤-catenin in the skin. Chronic activation of ␤-catenin in resting (telogen) hair follicles resulted in changes consistent with induction of an exaggerated, aberrant growth phase (anagen). Transient activation of ␤-catenin produced a normal anagen. Our data lend strong support to the notion that a Wnt/ ␤-catenin signal operating on hair follicle precursor cells serves as a crucial proximal signal for the telogen-anagen transition. Wnt family proteins function in short-range signaling. They regulate cell fate, adhesion, differentiation, proliferation, and motility, and many studies have demonstrated their critical roles in development (for review, see Peifer and Polakis 2000). Mutational defects in Wnt signaling have a major contributing role in a broad spectrum of cancers (Polakis 2000). At present, it appears many Wnts exert their effects, at least in part, through a "canonical" signaling pathway in which stabilization of the ␤-catenin protein is essential. Much of the ␤-catenin protein in the cell is associated with the cell membrane, where ␤-catenin binds to and links E-cadherin to the cytoskeleton through ␤-catenin's binding to ␣-catenin. A fraction of the ␤-catenin is free in the cytoplasm and/or nucleus. Normally, in the absence of Wnt signals, ␤-catenin is bound and negatively regulated by a protein complex that includes the adenomatous polyposis coli (APC) and axin tumor suppressor proteins as well as glycogen synthase kinase-3␤ (GSK-3␤; for review, see Peifer and Polakis 2000). This complex promotes phosphorylation of ␤-catenin at a number of N-terminal serine and threonine residues, and the phosphorylated ␤-catenin is ubiquitinated and subsequently degraded by the proteasome.Binding of Wnts to their cognate frizzled and low-density lipoprotein receptor-related protein receptor complexes on the cell surface leads to inhibition of GSK-3␤ activity and increased levels of free ␤-catenin in the cell (Peifer and Polakis 2000). In cancers, inactivating mutations in the APC or axin proteins or activating mutations affecting N-terminal phosphorylation sites in ␤-catenin lead to stabilization of ␤-catenin (Polakis 2000). Regardless of whether Wnt signals or mutational defects stabilize ␤-catenin, following its accumulation in the cell, ␤-catenin can complex in the nucleus with T cell factor/ lymphoid enhancer factor (TCF/LEF) transcription regulators, leading to activation of TCF-regulated genes (a list of candidate TCF target genes is provided at: http:// www.stanford.edu/∼rnusse/wntwindow.html).Wnt/␤-catenin signaling has been proposed to function in hair follicle morphogenesis and differentiation (Kishimoto et al. 2000;Fuchs et al. 2001;Millar 2002). Hair follicle morphogenesis is characterized by the downward growth of epithelial hair follicle precursor cells into the ...

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

“…Since mice undergo two sequential waves of hair growth before entering a prolonged telogen phase at 6 weeks of age (Muller-Rover et al, 2001;Stenn and Paus, 2001), we began the 4OHT treatment at 6 weeks of age to ensure that the follicles would be in telogen for at least 3 weeks after initiating the 4OHT treatment. No hair regrowth was observed in the skin of transgenic mice treated with ethanol alone or wild-type mice treated with 4OHT (data not shown), as previously reported (Van Mater et al, 2003;Lo Celso et al, 2004). In contrast, drastic changes were detected in the transgenic mice treated with 4OHT ( Figure 2).…”

“…The activation of Wnt/b-catenin signaling brings about similar phenotypes in adult epidermis (Gat et al, 1998;Van Mater et al, 2003;Lo Celso et al, 2004). The mice expressing stabilized b-catenin or b-cateninMer fusion protein show epidermal hyperplasia, hair follicle tumor-like outgrowth and precocious transition from telogen to anagen phase via activation of stem cells.…”

Hairless triggers reactivation of hair growth by promoting Wnt signaling

“…The demonstration that HR function in progenitor keratinocytes is sufficient for hair follicle regeneration led us to investigate whether HR regulates Wnt signaling, because activation of this pathway in these cells has been directly implicated in hair follicle regeneration (31)(32)(33)(34)(35). We examined expression of a Wnt-responsive gene, Axin2 (36)(37)(38), and found that Axin2 expression is not detected in Hr Ϫ/Ϫ hair follicles at anagen initiation (Fig.…”

Development and Homeostasis of the Skin Epidermis

“…Conditional deletion of b-catenin in adult mouse epidermis leads to HF degeneration and cyst formation, demonstrating the essential function of b-catenin in maintaining the identity of adult HF SCs (Lowry et al 2005). Increased levels of b-catenin in adult HF SCs results in the shortening of telogen and the acceleration of telogen to anagen transition (Van Mater et al 2003;Lo Celso et al 2004;Lowry et al 2005), with a concomitant increase in bulge SC proliferation (Lowry et al 2005). Transcriptional profiling of bulge SCs during telogen and anagen, as well as following b-catenin gain-of-function expression, identified a set of genes modulated by Wnt/b-catenin signaling and associated with anagen reentry.…”