title: Low levels of the reverse transactivator fail to induce target transgene expression in vascular smooth muscle cells.
abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disease with multiple features that are suggestive of premature aging. Most patients with HGPS carry a mutation on one of their copies of the LMNA gene. The LMNA gene encodes the lamin A and lamin C proteins, which are the major proteins of the nuclear lamina. The organs of the cardiovascular system are amongst those that are most severely affected in HGPS, undergoing a progressive depletion of vascular smooth muscle cells, and most children with HGPS die in their early teens from cardio-vascular disease and other complications from atherosclerosis. In this study, we developed a transgenic mouse model based on the tet-ON system to increase the understanding of the molecular mechanisms leading to the most lethal aspect of HGPS. To induce the expression of the most common HGPS mutation, LMNA c.1824C>T; p.G608G, in the vascular smooth muscle cells of the aortic arch and thoracic aorta, we used the previously described reverse tetracycline-controlled transactivator, sm22α-rtTA. However, the expression of the reverse sm22α-transactivator was barely detectable in the arteries, and this low level of expression was not sufficient to induce the expression of the target human lamin A minigene. The results from this study are important because they suggest caution during the use of previously functional transgenic animal models and emphasize the importance of assessing transgene expression over time.
authors.affiliation: Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institutet, Novum, Huddinge, Sweden.
authors.forename: Nikenza
authors.initials: N
authors.lastname: Viceconte
authors.affiliation: Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institutet, Novum, Huddinge, Sweden.
authors.forename: Tomás
authors.initials: T
authors.lastname: McKenna
authors.affiliation: Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institutet, Novum, Huddinge, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson
mesh_terms: D000293:Adolescent; D000818:Animals; D001013:Aorta, Thoracic / Q000196:embryology / Q000473:pathology; D002648:Child; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D034904:Lamin Type A / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D034881:Nuclear Lamina / Q000235:genetics* / Q000473:pathology; D011371:Progeria / Q000235:genetics* / Q000473:pathology
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A
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