title: Altered E-Cadherin Levels and Distribution in Melanocytes Precede Clinical Manifestations of Vitiligo.
abstract: Vitiligo is the most common depigmenting disorder resulting from the loss of melanocytes from the basal epidermal layer. The pathogenesis of the disease is likely multifactorial and involves autoimmune causes, as well as oxidative and mechanical stress. It is important to identify early events in vitiligo to clarify pathogenesis, improve diagnosis, and inform therapy. Here, we show that E-cadherin (Ecad), which mediates the adhesion between melanocytes and keratinocytes in the epidermis, is absent from or discontinuously distributed across melanocyte membranes of vitiligo patients long before clinical lesions appear. This abnormality is associated with the detachment of the melanocytes from the basal to the suprabasal layers in the epidermis. Using human epidermal reconstructed skin and mouse models with normal or defective Ecad expression in melanocytes, we demonstrated that Ecad is required for melanocyte adhesiveness to the basal layer under oxidative and mechanical stress, establishing a link between silent/preclinical, cell-autonomous defects in vitiligo melanocytes and known environmental stressors accelerating disease expression. Our results implicate a primary predisposing skin defect affecting melanocyte adhesiveness that, under stress conditions, leads to disappearance of melanocytes and clinical vitiligo. Melanocyte adhesiveness is thus a potential target for therapy aiming at disease stabilization.
authors: Institut Curie, Normal and Pathological Development of Melanocytes, Orsay, France; CNRS UMR3347, Orsay, France; INSERM U1021, Orsay, France; Equipe labellisée, Ligue Nationale contre le Cancer, Orsay, France.
authors: Roselyne Y
authors: RY
authors: Wagner
authors: Institut Curie, Normal and Pathological Development of Melanocytes, Orsay, France; CNRS UMR3347, Orsay, France; INSERM U1021, Orsay, France; Equipe labellisée, Ligue Nationale contre le Cancer, Orsay, France.
authors: Flavie
authors: F
authors: Luciani
authors: Department of Dermatology and Pediatric Dermatology, National Reference Centre for Rare Skin Disorders, Hôpital Saint-André Bordeaux, Bordeaux, France; INSERM U1035, University of Bordeaux, Bordeaux, France.
authors: Muriel
authors: M
authors: Cario-André
authors: Institut Curie, Normal and Pathological Development of Melanocytes, Orsay, France; CNRS UMR3347, Orsay, France; INSERM U1021, Orsay, France; Equipe labellisée, Ligue Nationale contre le Cancer, Orsay, France.
authors: Alain
authors: A
authors: Rubod
authors: Institut Curie, Normal and Pathological Development of Melanocytes, Orsay, France; CNRS UMR3347, Orsay, France; INSERM U1021, Orsay, France; Equipe labellisée, Ligue Nationale contre le Cancer, Orsay, France.
authors: Valérie
authors: V
authors: Petit
authors: Department of Dermatology, Mohammed V University, UFR of Dermatology, Rabat, Morocco.
authors: Laila
authors: L
authors: Benzekri
authors: Department of Dermatology and Pediatric Dermatology, National Reference Centre for Rare Skin Disorders, Hôpital Saint-André Bordeaux, Bordeaux, France; INSERM U1035, University of Bordeaux, Bordeaux, France.
authors: Khaled
authors: K
authors: Ezzedine
authors: Department of Pathology, Bordeaux University Hospital, Bordeaux, France.
authors: Sébastien
authors: S
authors: Lepreux
authors: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Eirikur
authors: E
authors: Steingrimsson
authors: Department of Dermatology and Pediatric Dermatology, National Reference Centre for Rare Skin Disorders, Hôpital Saint-André Bordeaux, Bordeaux, France; INSERM U1035, University of Bordeaux, Bordeaux, France.
authors: A
authors: A
authors: Taieb
authors: Department of Dermatology and Pediatric Dermatology, National Reference Centre for Rare Skin Disorders, Hôpital Saint-André Bordeaux, Bordeaux, France.
authors: Yvon
authors: Y
authors: Gauthier
authors: Institut Curie, Normal and Pathological Development of Melanocytes, Orsay, France; CNRS UMR3347, Orsay, France; INSERM U1021, Orsay, France; Equipe labellisée, Ligue Nationale contre le Cancer, Orsay, France. Electronic address: lionel.larue@curie.fr.
authors: Lionel
authors: L
authors: Larue
authors: Institut Curie, Normal and Pathological Development of Melanocytes, Orsay, France; CNRS UMR3347, Orsay, France; INSERM U1021, Orsay, France; Equipe labellisée, Ligue Nationale contre le Cancer, Orsay, France.
authors: Véronique
authors: V
authors: Delmas
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D015820:Cadherins / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D014820:Vitiligo / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D015820:Cadherins
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