title: Evidence for baseline retinal pigment epithelium pathology in the Trp1-Cre mouse.
abstract: The increasing popularity of the Cre/loxP recombination system has led to the generation of numerous transgenic mouse lines in which Cre recombinase is expressed under the control of organ- or cell-specific promoters. Alterations in retinal pigment epithelium (RPE), a multifunctional cell monolayer that separates the retinal photoreceptors from the choroid, are prevalent in the pathogenesis of a number of ocular disorders, including age-related macular degeneration. To date, six transgenic mouse lines have been developed that target Cre to the RPE under the control of various gene promoters. However, multiple lines of evidence indicate that high levels of Cre expression can be toxic to mammalian cells. In this study, we report that in the Trp1-Cre mouse, a commonly used transgenic Cre strain for RPE gene function studies, Cre recombinase expression alone leads to RPE dysfunction and concomitant disorganization of RPE layer morphology, large areas of RPE atrophy, retinal photoreceptor dysfunction, and microglial cell activation in the affected areas. The phenotype described herein is similar to previously published reports of conditional gene knockouts that used the Trp1-Cre mouse, suggesting that Cre toxicity alone could account for some of the reported phenotypes and highlighting the importance of the inclusion of Cre-expressing mice as controls in conditional gene targeting studies.
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Aristomenis
authors.initials: A
authors.lastname: Thanos
authors.forename: Yuki
authors.initials: Y
authors.lastname: Morizane
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Murakami
authors.forename: Andrea
authors.initials: A
authors.lastname: Giani
authors.forename: Dimosthenis
authors.initials: D
authors.lastname: Mantopoulos
authors.forename: Maki
authors.initials: M
authors.lastname: Kayama
authors.forename: Mi In
authors.initials: MI
authors.lastname: Roh
authors.forename: Norman
authors.initials: N
authors.lastname: Michaud
authors.forename: Basil
authors.initials: B
authors.lastname: Pawlyk
authors.forename: Michael
authors.initials: M
authors.lastname: Sandberg
authors.forename: Lucy H
authors.initials: LH
authors.lastname: Young
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Demetrios G
authors.initials: DG
authors.lastname: Vavvas
mesh_terms: D000818:Animals; D001284:Atrophy / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004596:Electroretinography / Q000379:methods; D005786:Gene Expression Regulation; D019426:Integrases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology; D008854:Microscopy, Electron; D010088:Oxidoreductases / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics; D058499:Retinal Dystrophies / Q000201:enzymology / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure
chemical_list: D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse; C045073:Cre recombinase; D019426:Integrases