title: Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice.
abstract: Harlequin ichthyosis (HI) is caused by loss-of-function mutations in the keratinocyte lipid transporter ABCA12. The patients often die in the first 1 or 2 weeks of life, although HI survivors' phenotypes improve within several weeks after birth. In order to clarify the mechanisms of phenotypic recovery, we studied grafted skin and keratinocytes from Abca12-disrupted (Abca12(-/-)) mice showing abnormal lipid transport. Abca12(-/-) neonatal epidermis showed significantly reduced total ceramide amounts and aberrant ceramide composition. Immunofluorescence and immunoblotting of Abca12(-/-) neonatal epidermis revealed defective profilaggrin/filaggrin conversion and reduced protein expression of the differentiation-specific molecules, loricrin, kallikrein 5, and transglutaminase 1, although their mRNA expression was up-regulated. In contrast, Abca12(-/-) skin grafts kept in a dry environment exhibited dramatic improvements in all these abnormalities. Increased transepidermal water loss, a parameter representing barrier defect, was remarkably decreased in grafted Abca12(-/-) skin. Ten-passage sub-cultured Abca12(-/-) keratinocytes showed restoration of intact ceramide distribution, differentiation-specific protein expression and profilaggrin/filaggrin conversion, which were defective in primary-cultures. Using cDNA microarray analysis, lipid transporters including four ATP-binding cassette transporters were up-regulated after sub-culture of Abca12(-/-) keratinocytes compared with primary-culture. These results indicate that disrupted keratinocyte differentiation during the fetal development is involved in the pathomechanism of HI and, during maturation, Abca12(-/-) epidermal keratinocytes regain normal differentiation processes. This restoration may account for the skin phenotype improvement observed in HI survivors.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Yanagi
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.forename: Junko
authors.initials: J
authors.lastname: Ishikawa
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakai
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyamura
authors.forename: Ayano
authors.initials: A
authors.lastname: Naoe
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitahara
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000254:growth & development* / Q000473:pathology / Q000637:transplantation; D005333:Fetus / Q000033:anatomy & histology / Q000502:physiology; D000091344:Filaggrin Proteins; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007381:Intermediate Filament Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: C473801:ABCA12 protein, human; D018528:ATP-Binding Cassette Transporters; C532573:Abca12 protein, mouse; D002518:Ceramides; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins