title: A transgenic mouse model with inducible Tyrosinase gene expression using the tetracycline (Tet-on) system allows regulated rescue of abnormal chiasmatic projections found in albinism.
abstract: Congenital defects in retinal pigmentation, as in oculocutaneous albinism Type I (OCA1), where tyrosinase is defective, result in visual abnormalities affecting the retina and pathways into the brain. Transgenic animals expressing a functional tyrosinase gene on an albino genetic background display a correction of all these abnormalities, implicating a functional role for tyrosinase in normal retinal development. To address the function of tyrosinase in the development of the mammalian visual system, we have generated a transgenic mouse model with inducible expression of the tyrosinase gene using the tetracycline (TET-ON) system. We have produced two types of transgenic mice: first, mice expressing the transactivator rtTA chimeric protein under the control of mouse tyrosinase promoter and its locus control region (LCR), and; second, transgenic mice expressing a mouse tyrosinase cDNA construct driven by a minimal promoter inducible by rtTA in the presence of doxycycline. Inducible experiments have been carried out with selected double transgenic mouse lines. Tyrosinase expression has been induced from early embryo development and its impact assessed with histological and biochemical methods in heterozygous and homozygous double transgenic individuals. We have found an increase of tyrosinase activity in the eyes of induced animals, compared with littermate controls. However, there was significant variability in the activation of this gene, as reported in analogous experiments. In spite of this, we could observe corrected uncrossed chiasmatic pathways, decreased in albinism, in animals induced from their first gestational week. These mice could be instrumental in revealing the role of tyrosinase in mammalian visual development.
authors.affiliation: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus de Cantoblanco, 28049 Madrid, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Giménez
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lavado
authors.forename: Patricia
authors.initials: P
authors.lastname: Giraldo
authors.forename: Patricia
authors.initials: P
authors.lastname: Cozar
authors.forename: Glen
authors.initials: G
authors.lastname: Jeffery
authors.forename: Lluís
authors.initials: L
authors.lastname: Montoliu
mesh_terms: D016115:Albinism, Oculocutaneous / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary / Q000378:metabolism; D005123:Eye / Q000737:chemistry / Q000201:enzymology; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006720:Homozygote; D008543:Melanins / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000235:genetics* / Q000378:metabolism; D009897:Optic Chiasm / Q000002:abnormalities* / Q000201:enzymology; D019574:Optic Nerve Neoplasms / Q000201:enzymology; D010957:Plasmids; D013752:Tetracycline / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; D008543:Melanins; D014442:Monophenol Monooxygenase; D013752:Tetracycline