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 language | English |
|---|---|
| Pages (from-to) | 106-118 |
| Number of pages | 13 |
| Journal | American Journal of Pathology |
| Volume | 177 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2010 Jan 1 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice
AU - Yanagi, Teruki
AU - Akiyama, Masashi
AU - Nishihara, Hiroshi
AU - Ishikawa, Junko
AU - Sakai, Kaori
AU - Miyamura, Yuki
AU - Naoe, Ayano
AU - Kitahara, Takashi
AU - Tanaka, Shinya
AU - Shimizu, Hiroshi
PY - 2010/1/1
Y1 - 2010/1/1
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2010.091120
DO - 10.2353/ajpath.2010.091120
M3 - Article
VL - 177
SP - 106
EP - 118
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 1
ER -