Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia
Autor(a) principal: | |
---|---|
Data de Publicação: | 2010 |
Outros Autores: | , , , , |
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. |
id |
RCAP_13c85901b66f14de17e4c058cd6bbf10 |
---|---|
oai_identifier_str |
oai:run.unl.pt:10362/24047 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
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 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://doi.org/10.1167/iovs.09-4892 |
url |
https://doi.org/10.1167/iovs.09-4892 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0146-0404 PURE: 3201621 http://www.scopus.com/inward/record.url?scp=77958126469&partnerID=8YFLogxK https://doi.org/10.1167/iovs.09-4892 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
8 application/pdf application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
mluisa.alvim@gmail.com |
_version_ |
1822233341624057856 |
dc.identifier.doi.none.fl_str_mv |
10.1167/iovs.09-4892 |