title: Transcription factor Ctip2 controls epidermal lipid metabolism and regulates expression of genes involved in sphingolipid biosynthesis during skin development.
abstract: The stratum corneum is composed of protein-enriched corneocytes embedded in an intercellular matrix of nonpolar lipids organized as lamellar layers and giving rise to epidermal permeability barrier (EPB). EPB defects have an important role in the pathophysiology of skin diseases such as eczema. The transcriptional control of skin lipid metabolism is poorly understood. We have discovered that mice lacking transcription factor COUP-TF-interacting protein 2 (Ctip2) exhibit EPB defects including altered keratinocyte terminal differentiation, delayed skin barrier development, and interrupted neutral lipid distribution in the epidermis. Here we adapted a targeted lipidomic approach using mass spectrometry and have determined that Ctip2(-/-) mice (germline deletion of the Ctip2 gene) display altered composition of major epidermal lipids, such as ceramides and sphingomyelins, compared with wild-type mice at different stages of skin development. Interestingly, expressions of several genes involved in skin sphingolipid biosynthesis and metabolism were altered in mutant skin. Ctip2 was found to be recruited to the promoter region of a subset of those genes, suggesting their possible direct regulation by Ctip2. Our results confirm an important role of Ctip2 in regulating skin lipid metabolism and indicate that profiling of epidermal sphingolipid could be useful for designing effective strategies to improve barrier dysfunctions.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, USA; Linus Pauling Institute, Corvallis, Oregon, USA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Kirkwood
authors.affiliation: Linus Pauling Institute, Corvallis, Oregon, USA.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Taylor
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, USA; Linus Pauling Institute, Corvallis, Oregon, USA.
authors.forename: Jan F
authors.initials: JF
authors.lastname: Stevens
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, USA; Molecular Cell Biology Program, Corvallis, Oregon, USA; Environmental Health Science Center, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Leid
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, USA; Molecular Cell Biology Program, Corvallis, Oregon, USA.
authors.forename: Gitali
authors.initials: G
authors.lastname: Ganguli-Indra
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, USA; Molecular Cell Biology Program, Corvallis, Oregon, USA; Environmental Health Science Center, Oregon State University, Corvallis, Oregon, USA; Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA. Electronic address: arup.indra@oregonstate.edu.
authors.forename: Arup K
authors.initials: AK
authors.lastname: Indra
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology; D002518:Ceramides / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D013107:Sphingolipids / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C511143:Bcl11b protein, mouse; D002518:Ceramides; D012097:Repressor Proteins; D013107:Sphingolipids; D013109:Sphingomyelins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins