Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina
The RLBP1 gene encodes the 36 kDa cellular retinaldehyde-binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in RLBP1 are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albes...
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ftunivzuerich:oai:www.zora.uzh.ch:210147 2024-06-23T07:54:48+00:00 Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina Schlegel, Domino K Ramkumar, Srinivasagan von Lintig, Johannes Neuhauss, Stephan C F 2021-10-20 application/pdf https://www.zora.uzh.ch/id/eprint/210147/ https://www.zora.uzh.ch/id/eprint/210147/1/elife-71473-v2.pdf https://doi.org/10.5167/uzh-210147 https://doi.org/10.7554/elife.71473 eng eng eLife Sciences Publications Ltd. https://www.zora.uzh.ch/id/eprint/210147/1/elife-71473-v2.pdf doi:10.5167/uzh-210147 doi:10.7554/elife.71473 info:pmid/34668483 urn:issn:2050-084X info:eu-repo/semantics/openAccess Creative Commons: Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/ Schlegel, Domino K; Ramkumar, Srinivasagan; von Lintig, Johannes; Neuhauss, Stephan C F (2021). Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina. eLife, 10:e71473. Institute of Molecular Life Sciences 570 Life sciences biology General Immunology and Microbiology General Biochemistry Genetics and Molecular Biology General Medicine General Neuroscience Journal Article PeerReviewed info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2021 ftunivzuerich https://doi.org/10.5167/uzh-21014710.7554/elife.71473 2024-05-29T01:11:41Z The RLBP1 gene encodes the 36 kDa cellular retinaldehyde-binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in RLBP1 are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albescens, fundus albipunctatus, and Newfoundland rod–cone dystrophy. However, the etiology of these retinal disorders is not well understood. Here, we generated homologous zebrafish models to bridge this knowledge gap. Duplication of the rlbp1 gene in zebrafish and cell-specific expression of the paralogs rlbp1a in the retinal pigment epithelium and rlbp1b in Müller glial cells allowed us to create intrinsically cell type-specific knockout fish lines. Using rlbp1a and rlbp1b single and double mutants, we investigated the pathological effects on visual function. Our analyses revealed that rlbp1a was essential for cone photoreceptor function and chromophore metabolism in the fish eyes. rlbp1a-mutant fish displayed reduced chromophore levels and attenuated cone photoreceptor responses to light stimuli. They accumulated 11-cis and all-trans-retinyl esters which displayed as enlarged lipid droplets in the RPE reminiscent of the subretinal yellow-white lesions in patients with RLBP1 mutations. During aging, these fish developed retinal thinning and cone and rod photoreceptor dystrophy. In contrast, rlbp1b mutants did not display impaired vision. The double mutant essentially replicated the phenotype of the rlbp1a single mutant. Together, our study showed that the rlbp1a zebrafish mutant recapitulated many features of human blinding diseases caused by RLBP1 mutations and provided novel insights into the pathways for chromophore regeneration of cone photoreceptors. Article in Journal/Newspaper Newfoundland University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
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University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
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ftunivzuerich |
language |
English |
topic |
Institute of Molecular Life Sciences 570 Life sciences biology General Immunology and Microbiology General Biochemistry Genetics and Molecular Biology General Medicine General Neuroscience |
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Institute of Molecular Life Sciences 570 Life sciences biology General Immunology and Microbiology General Biochemistry Genetics and Molecular Biology General Medicine General Neuroscience Schlegel, Domino K Ramkumar, Srinivasagan von Lintig, Johannes Neuhauss, Stephan C F Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
topic_facet |
Institute of Molecular Life Sciences 570 Life sciences biology General Immunology and Microbiology General Biochemistry Genetics and Molecular Biology General Medicine General Neuroscience |
description |
The RLBP1 gene encodes the 36 kDa cellular retinaldehyde-binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in RLBP1 are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albescens, fundus albipunctatus, and Newfoundland rod–cone dystrophy. However, the etiology of these retinal disorders is not well understood. Here, we generated homologous zebrafish models to bridge this knowledge gap. Duplication of the rlbp1 gene in zebrafish and cell-specific expression of the paralogs rlbp1a in the retinal pigment epithelium and rlbp1b in Müller glial cells allowed us to create intrinsically cell type-specific knockout fish lines. Using rlbp1a and rlbp1b single and double mutants, we investigated the pathological effects on visual function. Our analyses revealed that rlbp1a was essential for cone photoreceptor function and chromophore metabolism in the fish eyes. rlbp1a-mutant fish displayed reduced chromophore levels and attenuated cone photoreceptor responses to light stimuli. They accumulated 11-cis and all-trans-retinyl esters which displayed as enlarged lipid droplets in the RPE reminiscent of the subretinal yellow-white lesions in patients with RLBP1 mutations. During aging, these fish developed retinal thinning and cone and rod photoreceptor dystrophy. In contrast, rlbp1b mutants did not display impaired vision. The double mutant essentially replicated the phenotype of the rlbp1a single mutant. Together, our study showed that the rlbp1a zebrafish mutant recapitulated many features of human blinding diseases caused by RLBP1 mutations and provided novel insights into the pathways for chromophore regeneration of cone photoreceptors. |
format |
Article in Journal/Newspaper |
author |
Schlegel, Domino K Ramkumar, Srinivasagan von Lintig, Johannes Neuhauss, Stephan C F |
author_facet |
Schlegel, Domino K Ramkumar, Srinivasagan von Lintig, Johannes Neuhauss, Stephan C F |
author_sort |
Schlegel, Domino K |
title |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_short |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_full |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_fullStr |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_full_unstemmed |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_sort |
disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
publisher |
eLife Sciences Publications Ltd. |
publishDate |
2021 |
url |
https://www.zora.uzh.ch/id/eprint/210147/ https://www.zora.uzh.ch/id/eprint/210147/1/elife-71473-v2.pdf https://doi.org/10.5167/uzh-210147 https://doi.org/10.7554/elife.71473 |
genre |
Newfoundland |
genre_facet |
Newfoundland |
op_source |
Schlegel, Domino K; Ramkumar, Srinivasagan; von Lintig, Johannes; Neuhauss, Stephan C F (2021). Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina. eLife, 10:e71473. |
op_relation |
https://www.zora.uzh.ch/id/eprint/210147/1/elife-71473-v2.pdf doi:10.5167/uzh-210147 doi:10.7554/elife.71473 info:pmid/34668483 urn:issn:2050-084X |
op_rights |
info:eu-repo/semantics/openAccess Creative Commons: Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/ |
op_doi |
https://doi.org/10.5167/uzh-21014710.7554/elife.71473 |
_version_ |
1802647066615218176 |