Distinct Functions for Wnt/β-Catenin in Hair Follicle Stem Cell Proliferation and Survival and Interfollicular Epidermal Homeostasis

Abstract

SUMMARY Wnt/β-catenin signaling is a central regulator of adult stem cells. Variable sensitivity of Wnt reporter transgenes, β-catenin’s dual roles in adhesion and signaling, and hair follicle degradation and inflammation resulting from broad deletion of epithelial β-catenin, have precluded clear understanding of Wnt/β-catenin’s functions in adult skin stem cells. By inducibly deleting β-catenin globally in skin epithelia, only in hair follicle stem cells, or only in interfollicular epidermis, and comparing the phenotypes with those caused by ectopic expression of the Wnt/β-catenin inhibitor Dkk1, we show that this pathway is necessary for hair follicle stem cell proliferation. However, β-catenin is not required within hair follicle stem cells for their maintenance, and follicles resume proliferating after removal of ectopic Dkk1, indicating persistence of functional progenitors. We further unexpectedly discovered a broader role for Wnt/β-catenin signaling in contributing to progenitor cell proliferation in non-hairy epithelia and interfollicular epidermis under homeostatic, but not inflammatory, conditions.

To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease

“…16 In mice, deactivation of b-catenin led to a thinner epithelium in the footpad and tongue. Indeed, terminal differentiation of suprabasalar structures, like the filiform papillae of the tongue, did not occur after inhibition of b-catenin.…”

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

“…In contrast, in vivo, the TCF3/4-high stem cells can persist for months in the absence of b-catenin, but the cells are unable to induce hair lineage differentiation (Choi et al 2013;Lien et al 2014). Moreover, when stimulated by plucking the old hair formed prior to Ctnnb1 ablation, b-catenin-deficient HFSCs proliferate, move upward, and promote sebocyte differentiation, resulting in an enlarged sebaceous gland (Lien et al 2014).…”

“…Another possibility is that growth inhibitory signals from neighboring wild-type basal epidermal progenitors provide negative cues to adjacent Ctnnb1-null progenitors, which might restrict their otherwise hyperproliferative growth. Alternatively, there could be fundamental differences between nonhairy and hairy skin (Huelsken et al 2001;Nguyen et al 2009;Choi et al 2013;Lim et al 2013;Lien et al 2014). When taken together with additional ambiguities surrounding the extent to which Axin2 and b-catenin levels are pure readouts for Wnt signaling as well as the caveats discussed above regarding adult mouse epidermis as a model for stem cell biology, it will not be a simple task to sift through the plethora of possible mechanisms underlying Wnt/b-catenin signaling in the epidermis.…”

WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

“…Interestingly, these Axin2 + cells are themselves the source of WNT ligands in the IFE, where a high level of secreted WNT inhibitors in the suprabasal layers of the epidermis creates a gradient that restricts autocrine WNT signaling to the basal layer , in effect creating spatial self-organization within the epidermis (Clevers, et al 2014). This 6 is supported by additional in vivo work showing that β-catenin is required for epidermal proliferation and SC maintenance in the IFE (Choi, et al 2013;Jensen, et al 2009). Furthermore, the WNT/β-catenin pathway also maintains human IFE SC populations in vitro (Zhu and Watt 1999).…”

“…Furthermore, the WNT/β-catenin pathway also maintains human IFE SC populations in vitro (Zhu and Watt 1999). Inducible reduction of WNT/β-catenin signaling in murine IFE inhibited proliferation under homeostatic conditions, but is not required for long-term maintenance of the IFE, nor needed for inflammatory-induced hyper-proliferation (Choi, et al 2013). This work suggests that WNT signaling has highly specialised functions in murine IFE, but the precise role of the network within specific regions and SC populations of human skin, still remains to be determined.…”