title: CCN3 controls 3D spatial localization of melanocytes in the human skin through DDR1.
abstract: Melanocytes reside within the basal layer of the human epidermis, where they attach to the basement membrane and replicate at a rate proportionate to that of keratinocytes, maintaining a lifelong stable ratio. In this study, we report that coculturing melanocytes with keratinocytes up-regulated CCN3, a matricellular protein that we subsequently found to be critical for the spatial localization of melanocytes to the basement membrane. CCN3 knockdown cells were dissociated either upward to the suprabasal layers of the epidermis or downward into the dermis. The overexpression of CCN3 increased adhesion to collagen type IV, the major component of the basement membrane. As the receptor responsible for CCN3-mediated melanocyte localization, we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that acts as a collagen IV adhesion receptor. DDR1 knockdown decreased melanocyte adhesion to collagen IV and shifted melanocyte localization in a manner similar to CCN3 knockdown. These results demonstrate an intricate and necessary communication between keratinocytes and melanocytes in maintaining normal epidermal homeostasis.
authors.affiliation: Molecular and Cellular Oncogenesis Program and 2Immunology Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Fukunaga-Kalabis
authors.forename: Gabriela
authors.initials: G
authors.lastname: Martinez
authors.forename: Zhao-Jun
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Jiri
authors.initials: J
authors.lastname: Kalabis
authors.forename: Paul
authors.initials: P
authors.lastname: Mrass
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.forename: Sue M
authors.initials: SM
authors.lastname: Firth
authors.forename: Nathalie
authors.initials: N
authors.lastname: Planque
authors.forename: Bernard
authors.initials: B
authors.lastname: Perbal
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D001485:Basement Membrane / Q000166:cytology; D002448:Cell Adhesion; D002465:Cell Movement; D055513:Connective Tissue Growth Factor; D000070819:Discoidin Domain Receptor 1; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D008544:Melanocytes / Q000166:cytology*; D055514:Nephroblastoma Overexpressed Protein; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D012867:Skin / Q000166:cytology*
chemical_list: C526317:CCN2 protein, human; C526319:CCN3 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases