title: A conditional transgenic mouse line for targeted expression of the stem cell marker LGR5.
abstract: LGR5 is a known marker of embryonic and adult stem cells in several tissues. In a mouse model, Lgr5+ cells have shown tumour-initiating properties, while in human cancers, such as basal cell carcinoma and colon cancer, LGR5 expression levels are increased: however, the effect of increased LGR5 expression is not fully understood. To study the effects of elevated LGR5 expression levels we generated a novel tetracycline-responsive, conditional transgenic mouse line expressing human LGR5, designated TRELGR5. In this transgenic line, LGR5 expression can be induced in any tissue depending on the expression pattern of the chosen transcriptional regulator. For the current study, we used transgenic mice with a tetracycline-regulated transcriptional transactivator linked to the bovine keratin 5 promoter (K5tTA) to drive expression of LGR5 in the epidermis. As expected, expression of human LGR5 was induced in the skin of double transgenic mice (K5tTA;TRELGR5). Inducing LGR5 expression during embryogenesis and early development resulted in macroscopically and microscopically detectable phenotypic changes, including kink tail, sparse fur coat and enlarged sebaceous glands. The fur and sebaceous gland phenotypes were reversible upon discontinued expression of transgenic LGR5, but this was not observed for the kink tail phenotype. There were no apparent phenotypic changes if LGR5 expression was induced at three weeks of age. The results demonstrate that increased expression of LGR5 during embryogenesis and the neonatal period alter skin development and homeostasis.
authors.affiliation: Center for Innovative Medicine and Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Department of Genetics and Cancer Stem Cell Innovation Centre, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway. Electronic address: jens.henrik.norum@ki.se.
authors.forename: Jens Henrik
authors.initials: JH
authors.lastname: Norum
authors.affiliation: Center for Innovative Medicine and Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Bergström
authors.affiliation: Center for Innovative Medicine and Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Agneta Birgitta
authors.initials: AB
authors.lastname: Andersson
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Raoul V
authors.initials: RV
authors.lastname: Kuiper
authors.affiliation: Center for Innovative Medicine and Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Hoelzl
authors.affiliation: Department of Genetics and Cancer Stem Cell Innovation Centre, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Therese
authors.initials: T
authors.lastname: Sørlie
authors.affiliation: Center for Innovative Medicine and Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgård
mesh_terms: D000818:Animals; D015415:Biomarkers; D002417:Cattle; D002454:Cell Differentiation; D002460:Cell Line; D004817:Epidermis / Q000196:embryology*; D005786:Gene Expression Regulation; D018859:Hair Follicle / Q000196:embryology*; D006801:Humans; D053569:Keratin-15 / Q000235:genetics; D053553:Keratin-6 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics; D010539:Permeability; D011401:Promoter Regions, Genetic; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D012627:Sebaceous Glands / Q000196:embryology*; D013234:Stem Cells / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D015415:Biomarkers; D053569:Keratin-15; D053553:Keratin-6; C492053:Krt15 protein, mouse; C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse
keywords: Hair follicle; LGR5; Sebaceous gland; Skin; Transgenic mouse; Wnt/PCP signalling