β-catenin Activity in the Dermal Papilla Regulates Morphogenesis and Regeneration of Hair

Hair follicle stem cells.

The Molecular Anatomy of Mouse Skin during Hair Growth and Rest.

p75 Neurotrophin Receptor-Mediated Signaling Promotes Human Hair Follicle Regression (Catagen)

Topical Inhibition of the Electron Transport Chain Can Stimulate the Hair Cycle

Skin Stem Cells in Silence, Action, and Cancer.

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

Many Paths to Alopecia via Compromised Regeneration of Hair Follicle Stem Cells

Role of Androgen in Mesenchymal Epithelial Interactions in Human Hair Follicle

Ligand-independent actions of the vitamin D receptor (VDR) are required for normal post-morphogenic hair cycles; however, the molecular mechanisms by which the VDR exerts these actions are not clear. Previous studies demonstrated impaired regulation of the canonical Wnt signaling pathway in primary keratinocytes lacking the VDR. To identify the key effector of canonical Wnt signaling that interacts with the VDR, GST pulldown studies were performed. A novel interaction between the VDR and LEF1 (lymphoid enhancer-binding factor-1) that is independent of β-catenin was identified. This interaction is dependent upon sequences within the N-terminal region of the VDR, a domain required for VDR-DNA interactions and normal hair cycling in mice. Mutation of specific residues within the N-terminal region of the VDR not only abrogated interactions between the VDR and LEF1 but also impaired the ability of the VDR to enhance Wnt signaling in vdr(-/-) primary keratinocytes. Thus, this study demonstrates a novel interaction between the VDR and LEF1 that is mediated by the DNA-binding domain of the VDR and that is required for normal canonical Wnt signaling in keratinocytes.

Nestin in Human Skin: Exclusive Expression in Intramesenchymal Skin Compartments and Regulation by Leptin

Human Perifollicular Macrophages Undergo Apoptosis, Express Wnt Ligands, and Switch their Polarization during Catagen

Keratinocyte stem cells, label-retaining cells and possible genome protection mechanisms.

Wnt Signaling, Lgr5, and Stem Cells in the Intestine and Skin

Promise of Human Induced Pluripotent Stem Cells in Skin Regeneration and Investigation

Hedgehog (HH) signaling in the epidermis is primarily mediated by the zinc finger transcription factors GLI1 and GLI2. Exquisite regulation of HH/GLI signaling is crucial for proper specification of the epidermal lineage and development of its derivatives, whereas dysregulation of HH/GLI signaling disrupts tissue homeostasis and causes basal cell carcinoma (BCC). Similarly, bone morphogenetic proteins (BMPs) and activins have been described as key signaling factors in the complex regulation of epidermal fate decisions, although their precise interplay with HH/GLI is largely elusive. Here we show that, in human epidermal cells, expression of the activin/BMP antagonist follistatin (FST) is predominantly up-regulated by the HH effector GLI2. Consistently, we found strong FST expression in the outer root sheath of human hair follicles and BCC. Detailed promoter analysis showed that two sequences with homology to the GLI consensus binding site are required for GLI2-mediated activation. Interestingly, activation of the FST promoter is highly GLI2-specific, because neither GLI1 nor GLI3 can significantly increase FST transcription. GLI2 specificity requires the presence of a 518-bp fragment in the proximal FST promoter region. On the protein level, sequences C-terminal to the zinc finger are responsible for GLI2-specific activation of FST transcription, pointing to the existence of GLI-interacting cofactors that modulate GLI target specificity. Our results reveal a key role of GLI2 in activation of the activin/BMP antagonist FST in response to HH signaling and provide new evidence for a regulatory interaction between HH and activin/BMP signaling in hair follicle development and BCC.