The Wnt/-catenin signaling pathway during hair follicle (HF) morphogenesis and regeneration. (a) Schematic of the canonical Wnt pathway (for more details, see http://www.stanford.edu/%7Ernusse/). In the absence of a Wnt signal, the excess of cytoplasmic -catenin is targeted for degradation through its association with a multiprotein complex. Upon binding Wnt, its activated receptor complex recruits certain key components of the -catenin degradation targeting machinery. Stabilized free cytoplasmic -catenin is now translocated to the nucleus, where it can associate with transcription factors of the LEF/TCF family to transactivate the expression of their target genes. (b) Loss- and gain-of-function studies in mice have highlighted the different functions of Wnt/-catenin signaling during morphogenesis and adult skin homeostasis. During HF morphogenesis, Wnt/-catenin is required to specify the HF (placode) fate in the undifferentiated basal epidermis. During the adult hair cycle, Wnt/-catenin is required to maintain HF stem cell (SC) identity. As judged by a Wnt reporter transgene, an increase in Wnt signaling promotes SC activation to initiate the growth of a new hair during the telogen-to-anagen transition. An even stronger signal appears to be involved later at the transition of matrix cells to commit to terminally differentiate specifically along the hair shaft lineage. (c) When a constitutively active form of -catenin is expressed for sustained periods in skin epidermis, mice develop de novo HFs from the interfollicular epidermis (IFE), outer root sheath (ORS), and sebaceous glands (SGs). Eventually, these mice develop HF tumors called pilomatricoma, which consist of immortalized matrix-like cells at the periphery, and pure hair cells in the centers (no inner root sheath or companion layer cells). Visualization was enhanced by breeding the K14-N mice on a background of K14-GFP mice. (d) The different signal strengths of Wnt reporter gene activity, combined with the -catenin dosage dependency associated with these different outcomes in mice, can be explained by a model whereby the effective strength of Wnt signaling controls the behavior and fate of the follicle SC. Note: The so-called gradient of Wnt activity refers to the status of Tcf/Lef/-catenin transcriptional activity within the cell, which in fact could be achieved as a gradient, without even involving a Wnt per se. DP, dermal papilla.

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Epidermal stem cells of the skin. - National Center for ...

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