title: Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery.
abstract: The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS). To date, the molecular mechanism underlying the symptoms characterizing SLS has been poorly understood. Using Aldh3a2(-/-) mice, we found here that Aldh3a2 was the major FALDH active in undifferentiated keratinocytes. Long-chain base metabolism was greatly impaired in Aldh3a2(-/-) keratinocytes. Phenotypically, the intercellular spaces were widened in the basal layer of the Aldh3a2(-/-) epidermis due to hyperproliferation of keratinocytes. Furthermore, oxidative stress-induced genes were up-regulated in Aldh3a2(-/-) keratinocytes. Upon keratinocyte differentiation, the activity of another FALDH, Aldh3b2, surpassed that of Aldh3a2 As a result, Aldh3a2(-/-) mice were indistinguishable from wild-type mice in terms of their whole epidermis FALDH activity, and their skin barrier function was uncompromised under normal conditions. However, perturbation of the stratum corneum caused increased transepidermal water loss and delayed barrier recovery in Aldh3a2(-/-) mice. In conclusion, Aldh3a2(-/-) mice replicated some aspects of SLS symptoms, especially at the basal layer of the epidermis. Our results suggest that hyperproliferation of keratinocytes via oxidative stress responses may partly contribute to the ichthyosis symptoms of SLS.
authors.affiliation: From the Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Naganuma
authors.affiliation: From the Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Takagi
authors.affiliation: From the Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Kanetake
authors.affiliation: From the Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kitamura
authors.affiliation: the Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan, and.
authors.forename: Satoko
authors.initials: S
authors.lastname: Hattori
authors.affiliation: the Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan, and the Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.affiliation: From the Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sassa
authors.affiliation: From the Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan, kihara@pharm.hokudai.ac.jp.
authors.forename: Akio
authors.identifier: http://orcid.org/0000-0001-5889-0788
authors.initials: A
authors.lastname: Kihara
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002463:Cell Membrane Permeability; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016111:Sjogren-Larsson Syndrome / Q000209:etiology / Q000473:pathology*; D012867:Skin / Q000378:metabolism / Q000473:pathology*
chemical_list: D012333:RNA, Messenger; C000596780:ALDH3B2 protein, mouse; D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase
keywords: ceramide; epidermis; gene knockout; genetic disease; keratinocyte; lipid; lipid ether; lipid metabolism; oxidative stress; sphingolipid