Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia

Detalhes bibliográficos
Autor(a) principal: Tolmachova, Tanya
Data de Publicação: 2010
Outros Autores: Wavre-Shapton, Silene T., Barnard, Alun R., MacLaren, Robert E., Futter, Clare E., Seabra, Miguel C.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
DOI: 10.1167/iovs.09-4892
Texto Completo: https://doi.org/10.1167/iovs.09-4892
Resumo: PURPOSE. Choroideremia (CHM) is a progressive X-linked degeneration of three ocular layers (photoreceptors, retinal pigment epithelium, and choroid), with a complex and still largely unclear pathogenesis. To investigate the pathophysiology of CHM, the authors engineered mice with a cell type-specific Chm/Rep1 knockout (KO). METHODS. A mouse line carrying a conditional allele ChmFlox was crossed with the transgenic line IRBP-Cre to achieve Chm KO, specifically in the photoreceptor layer, and Tyr-Cre to produce Chm KO, specifically in the retinal pigment epithelial and other pigmented cells. ChmFlox, Tyr-Cre+ and ChmFlox, IRBP-Cre+ mice were mated to produce mice with Chm KO in both layers. All mouse lines were studied by histology, electron microscopy, electroretinography (ERG), scanning laser ophthalmoscopy (SLO), and biochemical methods. RESULTS. In ChmFlox, IRBP-Cre+ mice the authors observed the progressive degeneration of photoreceptors in the presence of normal retinal pigment epithelium (RPE). ChmFlox, Tyr-Cre+ mice exhibited coat color dilution and pigment abnormalities of the RPE in the presence of an intact outer nuclear layer. In 6- to 8-month-old ChmFlox, Tyr-Cre+, IRBP-Cre+ mice, the degeneration of photoreceptors was accelerated compared with ChmFlox, IRBP-Cre+ mice but became leveled with age, such that it was comparable at 12 to 14 months. Detailed ERG and SLO analysis supported the histopathologic findings. CONCLUSIONS. Defects in photoreceptors and RPE can arise because of intrinsic defects caused cell autonomously by the Chm KO. However, when both photoreceptors and RPE are diseased, the dynamics of the degenerative process are altered. Photoreceptor functional deficit and cell death manifest much earlier, suggesting that the diseased RPE accelerates photoreceptor degeneration.
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spelling Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremiaRAB ESCORT PROTEIN-1LEBERS CONGENITAL AMAUROSISPARKINSONS-DISEASEZEBRAFISH MODELGENE-THERAPYGTPASESMICEACCUMULATIONMACROPHAGESMUTATIONOphthalmologySensory SystemsCellular and Molecular NeurosciencePURPOSE. Choroideremia (CHM) is a progressive X-linked degeneration of three ocular layers (photoreceptors, retinal pigment epithelium, and choroid), with a complex and still largely unclear pathogenesis. To investigate the pathophysiology of CHM, the authors engineered mice with a cell type-specific Chm/Rep1 knockout (KO). METHODS. A mouse line carrying a conditional allele ChmFlox was crossed with the transgenic line IRBP-Cre to achieve Chm KO, specifically in the photoreceptor layer, and Tyr-Cre to produce Chm KO, specifically in the retinal pigment epithelial and other pigmented cells. ChmFlox, Tyr-Cre+ and ChmFlox, IRBP-Cre+ mice were mated to produce mice with Chm KO in both layers. All mouse lines were studied by histology, electron microscopy, electroretinography (ERG), scanning laser ophthalmoscopy (SLO), and biochemical methods. RESULTS. In ChmFlox, IRBP-Cre+ mice the authors observed the progressive degeneration of photoreceptors in the presence of normal retinal pigment epithelium (RPE). ChmFlox, Tyr-Cre+ mice exhibited coat color dilution and pigment abnormalities of the RPE in the presence of an intact outer nuclear layer. In 6- to 8-month-old ChmFlox, Tyr-Cre+, IRBP-Cre+ mice, the degeneration of photoreceptors was accelerated compared with ChmFlox, IRBP-Cre+ mice but became leveled with age, such that it was comparable at 12 to 14 months. Detailed ERG and SLO analysis supported the histopathologic findings. CONCLUSIONS. Defects in photoreceptors and RPE can arise because of intrinsic defects caused cell autonomously by the Chm KO. However, when both photoreceptors and RPE are diseased, the dynamics of the degenerative process are altered. Photoreceptor functional deficit and cell death manifest much earlier, suggesting that the diseased RPE accelerates photoreceptor degeneration.NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)Centro de Estudos de Doenças Crónicas (CEDOC)RUNTolmachova, TanyaWavre-Shapton, Silene T.Barnard, Alun R.MacLaren, Robert E.Futter, Clare E.Seabra, Miguel C.2017-10-10T22:07:24Z2010-102010-10-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article8application/pdfapplication/pdfhttps://doi.org/10.1167/iovs.09-4892eng0146-0404PURE: 3201621http://www.scopus.com/inward/record.url?scp=77958126469&partnerID=8YFLogxKhttps://doi.org/10.1167/iovs.09-4892info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-05-22T17:28:09Zoai:run.unl.pt:10362/24047Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-05-22T17:28:09Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
title Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
spellingShingle Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
Tolmachova, Tanya
RAB ESCORT PROTEIN-1
LEBERS CONGENITAL AMAUROSIS
PARKINSONS-DISEASE
ZEBRAFISH MODEL
GENE-THERAPY
GTPASES
MICE
ACCUMULATION
MACROPHAGES
MUTATION
Ophthalmology
Sensory Systems
Cellular and Molecular Neuroscience
Tolmachova, Tanya
RAB ESCORT PROTEIN-1
LEBERS CONGENITAL AMAUROSIS
PARKINSONS-DISEASE
ZEBRAFISH MODEL
GENE-THERAPY
GTPASES
MICE
ACCUMULATION
MACROPHAGES
MUTATION
Ophthalmology
Sensory Systems
Cellular and Molecular Neuroscience
title_short Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
title_full Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
title_fullStr Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
title_full_unstemmed Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
title_sort Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
author Tolmachova, Tanya
author_facet Tolmachova, Tanya
Tolmachova, Tanya
Wavre-Shapton, Silene T.
Barnard, Alun R.
MacLaren, Robert E.
Futter, Clare E.
Seabra, Miguel C.
Wavre-Shapton, Silene T.
Barnard, Alun R.
MacLaren, Robert E.
Futter, Clare E.
Seabra, Miguel C.
author_role author
author2 Wavre-Shapton, Silene T.
Barnard, Alun R.
MacLaren, Robert E.
Futter, Clare E.
Seabra, Miguel C.
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
Centro de Estudos de Doenças Crónicas (CEDOC)
RUN
dc.contributor.author.fl_str_mv Tolmachova, Tanya
Wavre-Shapton, Silene T.
Barnard, Alun R.
MacLaren, Robert E.
Futter, Clare E.
Seabra, Miguel C.
dc.subject.por.fl_str_mv RAB ESCORT PROTEIN-1
LEBERS CONGENITAL AMAUROSIS
PARKINSONS-DISEASE
ZEBRAFISH MODEL
GENE-THERAPY
GTPASES
MICE
ACCUMULATION
MACROPHAGES
MUTATION
Ophthalmology
Sensory Systems
Cellular and Molecular Neuroscience
topic RAB ESCORT PROTEIN-1
LEBERS CONGENITAL AMAUROSIS
PARKINSONS-DISEASE
ZEBRAFISH MODEL
GENE-THERAPY
GTPASES
MICE
ACCUMULATION
MACROPHAGES
MUTATION
Ophthalmology
Sensory Systems
Cellular and Molecular Neuroscience
description PURPOSE. Choroideremia (CHM) is a progressive X-linked degeneration of three ocular layers (photoreceptors, retinal pigment epithelium, and choroid), with a complex and still largely unclear pathogenesis. To investigate the pathophysiology of CHM, the authors engineered mice with a cell type-specific Chm/Rep1 knockout (KO). METHODS. A mouse line carrying a conditional allele ChmFlox was crossed with the transgenic line IRBP-Cre to achieve Chm KO, specifically in the photoreceptor layer, and Tyr-Cre to produce Chm KO, specifically in the retinal pigment epithelial and other pigmented cells. ChmFlox, Tyr-Cre+ and ChmFlox, IRBP-Cre+ mice were mated to produce mice with Chm KO in both layers. All mouse lines were studied by histology, electron microscopy, electroretinography (ERG), scanning laser ophthalmoscopy (SLO), and biochemical methods. RESULTS. In ChmFlox, IRBP-Cre+ mice the authors observed the progressive degeneration of photoreceptors in the presence of normal retinal pigment epithelium (RPE). ChmFlox, Tyr-Cre+ mice exhibited coat color dilution and pigment abnormalities of the RPE in the presence of an intact outer nuclear layer. In 6- to 8-month-old ChmFlox, Tyr-Cre+, IRBP-Cre+ mice, the degeneration of photoreceptors was accelerated compared with ChmFlox, IRBP-Cre+ mice but became leveled with age, such that it was comparable at 12 to 14 months. Detailed ERG and SLO analysis supported the histopathologic findings. CONCLUSIONS. Defects in photoreceptors and RPE can arise because of intrinsic defects caused cell autonomously by the Chm KO. However, when both photoreceptors and RPE are diseased, the dynamics of the degenerative process are altered. Photoreceptor functional deficit and cell death manifest much earlier, suggesting that the diseased RPE accelerates photoreceptor degeneration.
publishDate 2010
dc.date.none.fl_str_mv 2010-10
2010-10-01T00:00:00Z
2017-10-10T22:07:24Z
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dc.language.iso.fl_str_mv eng
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http://www.scopus.com/inward/record.url?scp=77958126469&partnerID=8YFLogxK
https://doi.org/10.1167/iovs.09-4892
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dc.identifier.doi.none.fl_str_mv 10.1167/iovs.09-4892