-Catenin activity in the dermal papilla of the hair follicle regulates pigment-type switching

Cutaneous Biology Research Center, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA 02129, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2010; 107(50):21564-9. DOI: 10.1073/pnas.1007326107
Source: PubMed


The switch between black and yellow pigment is mediated by the interaction between Melanocortin receptor 1 (Mc1r) and its antagonist Agouti, but the genetic and developmental mechanisms that modify this interaction to obtain different coat color in distinct environments are poorly understood. Here, the role of Wnt/β-catenin signaling in the regulation of pigment-type switching was studied. Loss and gain of function of β-catenin in the dermal papilla (DP) of the hair follicle results in yellow and black animals, respectively. β-Catenin activity in the DP suppresses Agouti expression and activates Corin, a negative regulator of Agouti activity. In addition, β-catenin activity in the DP regulates melanocyte activity by a mechanism that is independent of both Agouti and Corin. The coordinate and inverse regulation of Agouti and Corin renders pelage pigmentation sensitive to changes in β-catenin activity in the DP that do not alter pelage structure. As a result, the signals that specify two biologically distinct quantitative traits are partially uncoupled despite their common regulation by the β-catenin pathway in the same cells.

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    • "To the best of our knowledge, this is the first study to show that ACT extract promotes hair growth through the activation of the Wnt/β-catenin pathway by enhancing β-catenin transcription and possibly by a mitogenic effect on dermal papilla cells. Because the Wnt/β-catenin pathway and β-catenin, in particular, play important roles in hair growth and NPC differentiation, we employed the pTOPFlash and NPC differentiation assays to screen materials for their abilities to activate this pathway (Jiro and Robert, 2000; Ito et al., 2007; David et al., 2010). From the results of these assays, the ACT extract was selected for further studies. "
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    ABSTRACT: Aims: The activation of Wnt/β-catenin signaling pathway plays an important role in hair follicle morphogenesis by stimulating bulge stem cells. This study was to obtain the activator of Wnt/β-catenin signaling pathway from natural products and to determine whether this activator can induce anagen hair growth in mice. Main methods: To identify materials that activate Wnt/β-catenin signaling pathway, 800 natural product extracts were screened using pTOPFlash assay and neural progenitor cell (NPC) differentiation assay. A selected extract was further tested for its effects on alkaline phosphatase (ALP) activity in human immortalized dermal papilla cell (iDPC) and the proliferation in iDPC and immortalized rat vibrissa DPC (RvDP). Finally, hair growth-promoting effects were evaluated in the dorsal skin of C57BL/6 mice. Key findings: Aconiti Ciliare Tuber (ACT) extract was one of the most active materials in both pTOPFlash and NPC differentiation assays. It promoted the differentiation of NPC cells even under proliferation-stimulating conditions (basic fibroblast growth factor: bFGF). It also increased ALP activity and proliferation of iDPC in dose-dependent manners, and it stimulated the induction of the anagen hair growth in C57BL/6 mice. These results suggest that ACT extract activates the Wnt/β-catenin signaling pathway by enhancing β-catenin transcription and has the potential to promote the induction of hair growth via activation of the stem cell activity of the dermal papilla cells. Significance: This is the first report indicating benefits of ACT extract in hair loss prevention by triggering the activation of Wnt/β-catenin signaling pathway and induction of the anagen hair growth in mice.
    Life sciences 11/2012; 91(s 19–20):935–943. DOI:10.1016/j.lfs.2012.09.008 · 2.70 Impact Factor
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    ABSTRACT: Coat colors are determined by melanin (eumelanin and pheomelanin). Melanin is synthesized in melanocytes and accumulates in special organelles, melanosomes, which upon maturation are transferred to keratinocytes. Melanocytes differentiate from undifferentiated precursors, called melanoblasts, which are derived from neural crest cells. Melanoblast/melanocyte proliferation and differentiation are regulated by the tissue environment, especially by keratinocytes, which synthesize endothelins, steel factor, hepatocyte growth factor, leukemia inhibitory factor and granulocyte-macrophage colony-stimulating factor. Melanocyte differentiation is also stimulated by alpha-melanocyte stimulating hormone; in the mouse, however, this hormone is likely carried through the bloodstream and not produced locally in the skin. Melanoblast migration, proliferation and differentiation are also regulated by many coat color genes otherwise known for their ability to regulate melanosome formation and maturation, pigment type switching and melanosome distribution and transfer. Thus, melanocyte proliferation and differentiation are not only regulated by genes encoding typical growth factors and their receptors but also by genes classically known for their role in pigment formation.
    Pigment Cell & Melanoma Research 03/2011; 24(3):462-78. DOI:10.1111/j.1755-148X.2011.00845.x · 4.62 Impact Factor
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    ABSTRACT: Corin is a transmembrane serine protease identified in the heart, where it converts natriuretic peptides from inactive precursors to mature active forms. Studies in animal models and patients with hypertension and heart disease demonstrate that corin is critical in maintaining normal blood pressure and cardiac function. Like many proteolytic enzymes, corin expression and activity are regulated. Cell biology experiments indicate that transcriptional control, intracellular protein trafficking, cell surface targeting, zymogen activation and ectodomain shedding are important mechanisms in regulating corin expression and activity in the heart. More recently, soluble corin was detected in human blood and its levels were found to be reduced in patients with heart failure (HF). These findings indicate that corin deficiency may be involved in the pathogenesis of HF and suggest that soluble corin may be used as a biomarker for the disease. In this review, we describe the function and regulation of corin and discuss recent studies of soluble corin in human blood and its potential use as a biomarker for HF.
    Clinica chimica acta; international journal of clinical chemistry 11/2011; 413(3-4):378-83. DOI:10.1016/j.cca.2011.10.032 · 2.82 Impact Factor
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