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Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors

PURPOSE: Loss of retinoschisin (RS1) function underlies X-linked retinoschisis (XLRS) pathology. In the retina, both photoreceptor inner segments and bipolar cells express RS1. However, the loss of RS1 function causes schisis primarily in the inner retina. To understand these cell type–specific phen...

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Autores principales: Vijayasarathy, Camasamudram, Zeng, Yong, Marangoni, Dario, Dong, Lijin, Pan, Zhuo-Hua, Simpson, Elizabeth M., Fariss, Robert N., Sieving, Paul A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9583743/
https://www.ncbi.nlm.nih.gov/pubmed/36227606
http://dx.doi.org/10.1167/iovs.63.11.8
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author Vijayasarathy, Camasamudram
Zeng, Yong
Marangoni, Dario
Dong, Lijin
Pan, Zhuo-Hua
Simpson, Elizabeth M.
Fariss, Robert N.
Sieving, Paul A.
author_facet Vijayasarathy, Camasamudram
Zeng, Yong
Marangoni, Dario
Dong, Lijin
Pan, Zhuo-Hua
Simpson, Elizabeth M.
Fariss, Robert N.
Sieving, Paul A.
author_sort Vijayasarathy, Camasamudram
collection PubMed
description PURPOSE: Loss of retinoschisin (RS1) function underlies X-linked retinoschisis (XLRS) pathology. In the retina, both photoreceptor inner segments and bipolar cells express RS1. However, the loss of RS1 function causes schisis primarily in the inner retina. To understand these cell type–specific phenotypes, we decoupled RS1 effects in bipolar cells from that in photoreceptors. METHODS: Bipolar cell transgene RS1 expression was achieved using two inner retina–specific promoters: (1) a minimal promoter engineered from glutamate receptor, metabotropic glutamate receptor 6 gene (mini-mGluR6/ Grm6) and (2) MiniPromoter (Ple155). Adeno-associated virus vectors encoding RS1 gene under either the mini-mGluR6 or Ple-155 promoter were delivered to the XLRS mouse retina through intravitreal or subretinal injection on postnatal day 14. Retinal structure and function were assessed 5 weeks later: immunohistochemistry for morphological characterization, optical coherence tomography and electroretinography (ERG) for structural and functional evaluation. RESULTS: Immunohistochemical analysis of RS1expression showed that expression with the MiniPromoter (Ple155) was heavily enriched in bipolar cells. Despite variations in vector penetrance and gene transfer efficiency across the injected retinas, those retinal areas with robust bipolar cell RS1 expression showed tightly packed bipolar cells with fewer cavities and marked improvement in inner retinal structure and synaptic function as judged by optical coherence tomography and electroretinography, respectively. CONCLUSIONS: These results demonstrate that RS1 gene expression primarily in bipolar cells of the XLRS mouse retina, independent of photoreceptor expression, can ameliorate retinoschisis structural pathology and provide further evidence of RS1 role in cell adhesion.
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spelling pubmed-95837432022-10-21 Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors Vijayasarathy, Camasamudram Zeng, Yong Marangoni, Dario Dong, Lijin Pan, Zhuo-Hua Simpson, Elizabeth M. Fariss, Robert N. Sieving, Paul A. Invest Ophthalmol Vis Sci Retinal Cell Biology PURPOSE: Loss of retinoschisin (RS1) function underlies X-linked retinoschisis (XLRS) pathology. In the retina, both photoreceptor inner segments and bipolar cells express RS1. However, the loss of RS1 function causes schisis primarily in the inner retina. To understand these cell type–specific phenotypes, we decoupled RS1 effects in bipolar cells from that in photoreceptors. METHODS: Bipolar cell transgene RS1 expression was achieved using two inner retina–specific promoters: (1) a minimal promoter engineered from glutamate receptor, metabotropic glutamate receptor 6 gene (mini-mGluR6/ Grm6) and (2) MiniPromoter (Ple155). Adeno-associated virus vectors encoding RS1 gene under either the mini-mGluR6 or Ple-155 promoter were delivered to the XLRS mouse retina through intravitreal or subretinal injection on postnatal day 14. Retinal structure and function were assessed 5 weeks later: immunohistochemistry for morphological characterization, optical coherence tomography and electroretinography (ERG) for structural and functional evaluation. RESULTS: Immunohistochemical analysis of RS1expression showed that expression with the MiniPromoter (Ple155) was heavily enriched in bipolar cells. Despite variations in vector penetrance and gene transfer efficiency across the injected retinas, those retinal areas with robust bipolar cell RS1 expression showed tightly packed bipolar cells with fewer cavities and marked improvement in inner retinal structure and synaptic function as judged by optical coherence tomography and electroretinography, respectively. CONCLUSIONS: These results demonstrate that RS1 gene expression primarily in bipolar cells of the XLRS mouse retina, independent of photoreceptor expression, can ameliorate retinoschisis structural pathology and provide further evidence of RS1 role in cell adhesion. The Association for Research in Vision and Ophthalmology 2022-10-13 /pmc/articles/PMC9583743/ /pubmed/36227606 http://dx.doi.org/10.1167/iovs.63.11.8 Text en Copyright 2022 The Authors https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License.
spellingShingle Retinal Cell Biology
Vijayasarathy, Camasamudram
Zeng, Yong
Marangoni, Dario
Dong, Lijin
Pan, Zhuo-Hua
Simpson, Elizabeth M.
Fariss, Robert N.
Sieving, Paul A.
Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors
title Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors
title_full Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors
title_fullStr Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors
title_full_unstemmed Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors
title_short Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors
title_sort targeted expression of retinoschisin by retinal bipolar cells in xlrs promotes resolution of retinoschisis cysts sans rs1 from photoreceptors
topic Retinal Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9583743/
https://www.ncbi.nlm.nih.gov/pubmed/36227606
http://dx.doi.org/10.1167/iovs.63.11.8
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