title: Generation of brain tumours in mice by Cre-mediated recombination of neural progenitors in situ with the tamoxifen metabolite endoxifen.
abstract: Targeted cell- or region-specific gene recombination is widely used in the functional analysis of genes implicated in development and disease. In the brain, targeted gene recombination has become a mainstream approach to study neurodegeneration or tumorigenesis. The use of the Cre-loxP system to study tumorigenesis in the adult central nervous system (CNS) can be limited, when the promoter (such as GFAP) is also transiently expressed during development, which can result in the recombination of progenies of different lineages. Engineering of transgenic mice expressing Cre recombinase fused to a mutant of the human oestrogen receptor (ER) allows the circumvention of transient developmental Cre expression by inducing recombination in the adult organism. The recombination of loxP sequences occurs only in the presence of tamoxifen. Systemic administration of tamoxifen can, however, exhibit toxicity and might also recombine unwanted cell populations if the promoter driving Cre expression is active at the time of tamoxifen administration. Here, we report that a single site-specific injection of an active derivative of tamoxifen successfully activates Cre recombinase and selectively recombines tumour suppressor genes in neural progenitor cells of the subventricular zone in mice, and we demonstrate its application in a model for the generation of intrinsic brain tumours.
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Benedykcinska
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Andreia
authors.initials: A
authors.lastname: Ferreira
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lau
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Broni
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Richard-Loendt
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Nico V
authors.initials: NV
authors.lastname: Henriquez
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK s.brandner@ucl.ac.uk.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D019426:Integrases / Q000235:genetics*; D051379:Mice; D058953:Neural Stem Cells / Q000473:pathology*; D011995:Recombination, Genetic; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; C045073:Cre recombinase; D019426:Integrases
keywords: Brain tumour; Cre recombination; Endoxifen; Tamoxifen; loxP system