title: Overexpression of Lamin B Receptor Results in Impaired Skin Differentiation.
abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a rare segmental progeroid disorder commonly caused by a point mutation in the LMNA gene that results in the increased activation of an intra-exonic splice site and the production of a truncated lamin A protein, named progerin. In our previous work, induced murine epidermal expression of this specific HGPS LMNA mutation showed impaired keratinocyte differentiation and upregulated lamin B receptor (LBR) expression in suprabasal keratinocytes. Here, we have developed a novel transgenic animal model with induced overexpression of LBR in the interfollicular epidermis. LBR overexpression resulted in epidermal hypoplasia, along with the downregulation and mislocalization of keratin 10, suggesting impaired keratinocyte differentiation. Increased LBR expression in basal and suprabasal cells did not coincide with increased proliferation. Similar to our previous report of HGPS mice, analyses of γH2AX, a marker of DNA double-strand breaks, revealed an increased number of keratinocytes with multiple foci in LBR-overexpressing mice compared with wild-type mice. In addition, suprabasal LBR-positive cells showed densely condensed and peripherally localized chromatin. Our results show a moderate skin differentiation phenotype, which indicates that upregulation of LBR is not the sole contributor to the HGPS phenotype.
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, SE-141 83, Sweden.
authors.forename: Agustín
authors.initials: A
authors.lastname: Sola Carvajal
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, SE-141 83, Sweden.
authors.forename: Tomás
authors.initials: T
authors.lastname: McKenna
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, SE-141 83, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Wallén Arzt
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, SE-141 83, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D040502:Calgranulin B / Q000378:metabolism; D002454:Cell Differentiation; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D034904:Lamin Type A / Q000378:metabolism; D008822:Mice, Transgenic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012867:Skin / Q000473:pathology*; D015854:Up-Regulation; D000097682:Lamin B Receptor
chemical_list: D040502:Calgranulin B; D004247:DNA; D034904:Lamin Type A; D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor; C576329:S100A9 protein, mouse