Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice

Teruki Yanagi, Masashi Akiyama, Hiroshi Nishihara, Junko Ishikawa, Kaori Sakai, Yuki Miyamura, Ayano Naoe, Takashi Kitahara, Shinya Tanaka, Hiroshi Shimizu

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)106-118
Number of pages13
JournalAmerican Journal of Pathology
Volume177
Issue number1
DOIs
Publication statusPublished - 2010 Jan 1
Externally publishedYes

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Lamellar Ichthyosis
Keratinocytes
Skin
Ceramides
Lipids
Epidermis
Survivors
Phenotype
Tissue Kallikreins
ATP-Binding Cassette Transporters
Microarray Analysis
Fetal Development
Oligonucleotide Array Sequence Analysis
Immunoblotting
Fluorescent Antibody Technique
Proteins
Parturition
Transplants
Messenger RNA
Mutation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice. / Yanagi, Teruki; Akiyama, Masashi; Nishihara, Hiroshi; Ishikawa, Junko; Sakai, Kaori; Miyamura, Yuki; Naoe, Ayano; Kitahara, Takashi; Tanaka, Shinya; Shimizu, Hiroshi.

In: American Journal of Pathology, Vol. 177, No. 1, 01.01.2010, p. 106-118.

Research output: Contribution to journalArticle

Yanagi, T, Akiyama, M, Nishihara, H, Ishikawa, J, Sakai, K, Miyamura, Y, Naoe, A, Kitahara, T, Tanaka, S & Shimizu, H 2010, 'Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice', American Journal of Pathology, vol. 177, no. 1, pp. 106-118. https://doi.org/10.2353/ajpath.2010.091120
Yanagi, Teruki ; Akiyama, Masashi ; Nishihara, Hiroshi ; Ishikawa, Junko ; Sakai, Kaori ; Miyamura, Yuki ; Naoe, Ayano ; Kitahara, Takashi ; Tanaka, Shinya ; Shimizu, Hiroshi. / Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice. In: American Journal of Pathology. 2010 ; Vol. 177, No. 1. pp. 106-118.
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