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Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death
Retinitis pigmentosa (RP), a retinal degenerative disease, is the leading cause of heritable blindness. Previously, we described that Arap1(−/−) mice develop a similar pattern of photoreceptor degeneration. Arap1 is an Arf-directed GTPase-activating protein shown to modulate actin cytoskeletal dynam...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346516/ https://www.ncbi.nlm.nih.gov/pubmed/35758026 http://dx.doi.org/10.1242/dmm.049343 |
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author | Shao, Andy Lopez, Antonio Jacobo Chen, JiaJia Tham, Addy Javier, Seanne Quiroz, Alejandra Frick, Sonia Levine, Edward M. Lloyd, K. C. Kent Leonard, Brian C. Murphy, Christopher J. Glaser, Thomas M. Moshiri, Ala |
author_facet | Shao, Andy Lopez, Antonio Jacobo Chen, JiaJia Tham, Addy Javier, Seanne Quiroz, Alejandra Frick, Sonia Levine, Edward M. Lloyd, K. C. Kent Leonard, Brian C. Murphy, Christopher J. Glaser, Thomas M. Moshiri, Ala |
author_sort | Shao, Andy |
collection | PubMed |
description | Retinitis pigmentosa (RP), a retinal degenerative disease, is the leading cause of heritable blindness. Previously, we described that Arap1(−/−) mice develop a similar pattern of photoreceptor degeneration. Arap1 is an Arf-directed GTPase-activating protein shown to modulate actin cytoskeletal dynamics. Curiously, Arap1 expression was detected in Müller glia and retinal pigment epithelium (RPE), but not the photoreceptors themselves. In this study, we generated conditional knockout mice for Müller glia/RPE, Müller glia and RPE via targeting Rlbp1, Glast and Vmd2 promoters, respectively, to drive Cre recombinase expression to knock out Arap1. Vmd2-Cre Arap1(tm1c/tm1c) and Rlbp1-Cre Arap1(tm1c/tm1c) mice, but not Glast-Cre Arap1(tm1c/tm1c) mice, recapitulated the phenotype originally observed in germline Arap1(−/−) mice. Mass spectrometry analysis of human ARAP1 co-immunoprecipitation identified candidate binding partners of ARAP1, revealing potential interactants involved in phagocytosis, cytoskeletal composition, intracellular trafficking and endocytosis. Quantification of outer segment phagocytosis in vivo demonstrated a clear phagocytic defect in Arap1(−/−) mice compared to Arap1(+/+) controls. We conclude that Arap1 expression in RPE is necessary for photoreceptor survival due to its indispensable function in RPE phagocytosis. This article has an associated First Person interview with the first author of the paper. |
format | Online Article Text |
id | pubmed-9346516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-93465162022-08-03 Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death Shao, Andy Lopez, Antonio Jacobo Chen, JiaJia Tham, Addy Javier, Seanne Quiroz, Alejandra Frick, Sonia Levine, Edward M. Lloyd, K. C. Kent Leonard, Brian C. Murphy, Christopher J. Glaser, Thomas M. Moshiri, Ala Dis Model Mech Research Article Retinitis pigmentosa (RP), a retinal degenerative disease, is the leading cause of heritable blindness. Previously, we described that Arap1(−/−) mice develop a similar pattern of photoreceptor degeneration. Arap1 is an Arf-directed GTPase-activating protein shown to modulate actin cytoskeletal dynamics. Curiously, Arap1 expression was detected in Müller glia and retinal pigment epithelium (RPE), but not the photoreceptors themselves. In this study, we generated conditional knockout mice for Müller glia/RPE, Müller glia and RPE via targeting Rlbp1, Glast and Vmd2 promoters, respectively, to drive Cre recombinase expression to knock out Arap1. Vmd2-Cre Arap1(tm1c/tm1c) and Rlbp1-Cre Arap1(tm1c/tm1c) mice, but not Glast-Cre Arap1(tm1c/tm1c) mice, recapitulated the phenotype originally observed in germline Arap1(−/−) mice. Mass spectrometry analysis of human ARAP1 co-immunoprecipitation identified candidate binding partners of ARAP1, revealing potential interactants involved in phagocytosis, cytoskeletal composition, intracellular trafficking and endocytosis. Quantification of outer segment phagocytosis in vivo demonstrated a clear phagocytic defect in Arap1(−/−) mice compared to Arap1(+/+) controls. We conclude that Arap1 expression in RPE is necessary for photoreceptor survival due to its indispensable function in RPE phagocytosis. This article has an associated First Person interview with the first author of the paper. The Company of Biologists Ltd 2022-07-25 /pmc/articles/PMC9346516/ /pubmed/35758026 http://dx.doi.org/10.1242/dmm.049343 Text en © 2022. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Shao, Andy Lopez, Antonio Jacobo Chen, JiaJia Tham, Addy Javier, Seanne Quiroz, Alejandra Frick, Sonia Levine, Edward M. Lloyd, K. C. Kent Leonard, Brian C. Murphy, Christopher J. Glaser, Thomas M. Moshiri, Ala Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death |
title | Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death |
title_full | Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death |
title_fullStr | Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death |
title_full_unstemmed | Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death |
title_short | Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death |
title_sort | arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346516/ https://www.ncbi.nlm.nih.gov/pubmed/35758026 http://dx.doi.org/10.1242/dmm.049343 |
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