title: Topobiology of human pigmentation: P-cadherin selectively stimulates hair follicle melanogenesis.
abstract: P-cadherin serves as a major topobiological cue in mammalian epithelium. In human hair follicles (HFs), it is prominently expressed in the inner hair matrix that harbors the HF pigmentary unit. However, the role of P-cadherin in normal human pigmentation remains unknown. As patients with mutations in the gene that encodes P-cadherin show hypotrichosis and fair hair, we explored the hypothesis that P-cadherin may control HF pigmentation. When P-cadherin was silenced in melanogenically active organ-cultured human scalp HFs, this significantly reduced HF melanogenesis and tyrosinase activity as well as gene and/or protein expression of gp100, stem cell factor, c-Kit, and microphthalmia-associated transcription factor (MITF), both in situ and in isolated human HF melanocytes. Instead, epidermal pigmentation was unaffected by P-cadherin knockdown in organ-cultured human skin. In hair matrix keratinocytes, P-cadherin silencing reduced plasma membrane β-catenin, whereas glycogen synthase kinase 3 beta (GSK3β) and phospho-β-catenin expression were significantly upregulated. This suggests that P-cadherin-GSK3β/Wnt signaling is required for maintaining the expression of MITF to sustain intrafollicular melanogenesis. Thus, P-cadherin-mediated signaling is a melanocyte subtype-specific topobiological regulator of normal human pigmentation, possibly via GSK3β-mediated canonical Wnt signaling.
authors: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors: Liat
authors: L
authors: Samuelov
authors: Eli
authors: E
authors: Sprecher
authors: Koji
authors: K
authors: Sugawara
authors: Suman K
authors: SK
authors: Singh
authors: Desmond J
authors: DJ
authors: Tobin
authors: Daisuke
authors: D
authors: Tsuruta
authors: Tamás
authors: T
authors: Bíró
authors: Jennifer E
authors: JE
authors: Kloepper
authors: Ralf
authors: R
authors: Paus
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018859:Hair Follicle / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000166:cytology* / Q000502:physiology*; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012880:Skin Pigmentation / Q000502:physiology*; D019089:Stem Cell Factor / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D019089:Stem Cell Factor; D058951:gp100 Melanoma Antigen; D014442:Monophenol Monooxygenase; D019009:Proto-Oncogene Proteins c-kit; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3