title: Involucrin-claudin-6 tail deletion mutant (CDelta206) transgenic mice: a model of delayed epidermal permeability barrier formation and repair.
abstract: Preterm birth is a major global health problem that results in a large number of infant deaths, many of which are attributable to the complications of an immature epidermal permeability barrier (EPB), for which there is currently no effective therapeutic option. The mammalian EPB is formed during development and is essential for survival as it maintains thermoregulation and hydration, and provides a defense against infection. Using transgenic mouse technology, we have demonstrated the importance of claudin (Cldn)-containing tight junctions (TJs) in epidermal differentiation and, in particular, that epidermal suprabasal overexpression of Cldn6 results in an EPB-deficient phenotype that phenocopies the dysfunctional EPB of premature human infants. In this study, we used the same approach to target a Cldn6 tail deletion mutant to the epidermis of mice [involucrin (Inv)-Cldn6-CDelta206 transgenic mice]. The Inv-Cldn6-CDelta206 transgenic mice displayed a developmental delay in EPB formation, as shown by the expression of keratins and Cldns, and by X-Gal penetration assays. Trans-epidermal water loss measurements and immunolocalization studies indicated that the epidermal differentiation program was also perturbed in postnatal Inv-Cldn6-CDelta206 transgenic mice resulting in a delayed maturation. Notably, however, expression/localization of epidermal differentiation and maturation markers, including Cldns, indicated that the transgenic epidermis matured and normalized by postnatal day 10, which is 3 days after the wild-type epidermis. Our results suggest that activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway and Cldn1 phosphorylation are associated with the repair and maturation of the skin barrier processes. These studies provide additional support for the crucial role of Cldns in epidermal differentiation, maturation and the formation of the EPB, and describe a novel animal model for evaluating postnatal epidermal maturation and therapies that may accelerate the process.
authors.affiliation: Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute, Ottawa, Ontario K1Y 8L6, Canada.
authors.forename: Adebola
authors.initials: A
authors.lastname: Enikanolaiye
authors.forename: Nathalie
authors.initials: N
authors.lastname: Larivière
authors.forename: Tammy-Claire
authors.initials: TC
authors.lastname: Troy
authors.forename: Azadeh
authors.initials: A
authors.lastname: Arabzadeh
authors.forename: Elif
authors.initials: E
authors.lastname: Atasoy
authors.forename: Kursad
authors.initials: K
authors.lastname: Turksen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation; D062445:Claudin-1; D057167:Claudins; D004817:Epidermis / Q000201:enzymology / Q000254:growth & development / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005697:Galactosides / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D010539:Permeability; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism*; D021381:Protein Transport; D017384:Sequence Deletion / Q000235:genetics*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D014945:Wound Healing
chemical_list: D015415:Biomarkers; C568108:CLDN1 protein, human; D027682:Cation Transport Proteins; D062445:Claudin-1; D057167:Claudins; C568113:Cldn1 protein, mouse; D005697:Galactosides; D007211:Indoles; D008565:Membrane Proteins; D011498:Protein Precursors; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C032253:involucrin; D048049:Extracellular Signal-Regulated MAP Kinases; C122101:claudin 6; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside