Hairy Math: Add Wnt-3a to Multiply Bulge Cells

Canonical Wnt signals are important for activation of epithelial skin stem cells, but the role of individual Wnt ligands remains uncertain. Ouji et al. demonstrate a key role for Wnt-3a in partial maintenance and long-term expansion of epithelial skin stem cells in vitro. They also report a method for expanding these cells in vitro without feeder cells. The role of canonical Wnt-β-catenin signaling in hair follicle and epithelial stem cell biology has intrigued investigators for years. Numerous studies have implicated this signaling cascade in different aspects of hair follicle morphogenesis, regulation of the hair follicle cycling, and promotion of hair growth (Lien and Fuchs, 2014). However, given the large number of mammalian Wnt ligands (nineteen) and Fzd receptors (ten) in the context of a complex interplay between activating and inhibiting molecules within this pathway (Clevers et al., 2014), the precise role of individual Wnt molecules remains largely undefined. In the current issue of the JID, Ouji et al. (Ouji et al., 2014) shed light on the role of Wnt-3a in partial maintenance and long-term expansion of bulge stem cells in vitro. The canonical Wnt-β-catenin pathway is among the most highly conserved signaling cascades in mammalian development, organogenesis, and tissue homeostasis (Clevers et al., 2014). In the absence of a canonical Wnt signal, a degradation complex, consisting of APC, axin, and GSK3β, sequesters cytosolic β-catenin. In this complex, GSK-3-β kinase phosphorylates β-catenin at the N-terminus and marks it for ubiquitylation and proteasomal degradation. Simultaneously, members of the Lymphocyte Enhancement Factor/T Cell Factor (LEF/TCF) family of transcription factors keep Wnt target genes inactive by interacting with TLE (Groucho) co-repressor protein on promoters. The binding of a member of the Wnt family of secreted glycoproteins to the frizzled (Fzd) receptors and the LRP co-receptors on the cell surface leads to inactivation of GSK-3-β. As a result, β-Catenin is no longer phsosphorylated or degraded. Non-phosphorylated β-catenin accumulates in the cytoplasm, translocates to the nucleus, binds to LEF/TCF, directly displaces TLE, and induces expression of Wnt-β-catenin target genes. This signaling pathway can be modulated by a number of extracellular inhibitory molecules. These include the DKK family of secreted proteins, which interact with LRP6 co-receptor and Kremen, secreted frizzledUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence: Luis A. Garza, Department of Dermatology, Johns Hopkins University School of Medicine, CRB II Suite 204, 1551 Orleans Street, Baltimore, Maryland 21231, USA. [email protected]. HHS Public Access Author manuscript J Invest Dermatol. Author manuscript; available in PMC 2015 December 01. Published in final edited form as: J Invest Dermatol. 2015 June ; 135(6): 1481–1483. doi:10.1038/jid.2014.545. A uhor M anscript