title: Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin.
abstract: We have hypothesised that melanocytes disappear in vitiligo because they are weakly attached to the epidermal basal membrane (melanocytorrhagy). In the epidermis, attachment of melanocytes to collagen IV is mediated through DDR1, which is under the control of CCN3. DDR1 genetic variants have been associated with vitiligo in patients of different ethnic origin. In vitro studies have shown that inhibition of CCN3 induces the detachment of melanocytes. We have studied in parallel the expression of CCN3 and DDR1 in lesional and perilesional skin of patients with vitiligo and the impact of the silencing of CCN3 and DDR1 in normal human melanocytes on their behaviour in epidermal reconstructs. Our in vivo study provides evidence of a dysregulation of the DDR1-CCN3 interaction in vitiligo skin as melanocytes remaining in perilesional skin did not express CCN3. Expression of DDR1 was decreased in lesional versus perilesional vitiligo skin in the majority of patients, and the expression of collagen IV was found decreased in all patients. Silencing of CCN3 in melanocytes induced a significant inhibition of cell adhesion to collagen IV whereas melanocytes transduced with shDDR1 still adhered well on collagen IV and did not increase melanocyte loss in epidermal reconstructs as compared with normal melanocytes. Melanocyte detachment was observed but not in all reconstructs using CCN3 silenced melanocytes. Overall, our study confirms that a downregulation of CCN3 is implicated in melanocyte adhesion in part through DDR1. In vitiligo skin, the interaction of CCN3 with other molecules, such as TGFβ and CCN2, needs to be addressed.
authors.affiliation: Inserm 1035, University V Segalen, Bordeaux, France.
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Ricard
authors.forename: Catherine
authors.initials: C
authors.lastname: Pain
authors.forename: Alexia
authors.initials: A
authors.lastname: Daubos
authors.forename: Khaled
authors.initials: K
authors.lastname: Ezzedine
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lamrissi-Garcia
authors.forename: Alice
authors.initials: A
authors.lastname: Bibeyran
authors.forename: Veronique
authors.initials: V
authors.lastname: Guyonnet-Dupérat
authors.forename: Alain
authors.initials: A
authors.lastname: Taieb
authors.forename: Muriel
authors.initials: M
authors.lastname: Cario-André
mesh_terms: D000328:Adult; D002448:Cell Adhesion; D024141:Collagen Type IV / Q000378:metabolism; D000070819:Discoidin Domain Receptor 1; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism*; D008875:Middle Aged; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D014820:Vitiligo / Q000378:metabolism*
chemical_list: C526319:CCN3 protein, human; D024141:Collagen Type IV; D055514:Nephroblastoma Overexpressed Protein; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases