mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish.
The retinal pigment epithelium (RPE) plays numerous critical roles in maintaining vision and this is underscored by the prevalence of degenerative blinding diseases like age-related macular degeneration (AMD), in which visual impairment is caused by progressive loss of RPE cells. In contrast to mamm...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-03-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1009628 |
| _version_ | 1797903309622738944 |
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| author | Fangfang Lu Lyndsay L Leach Jeffrey M Gross |
| author_facet | Fangfang Lu Lyndsay L Leach Jeffrey M Gross |
| author_sort | Fangfang Lu |
| collection | DOAJ |
| description | The retinal pigment epithelium (RPE) plays numerous critical roles in maintaining vision and this is underscored by the prevalence of degenerative blinding diseases like age-related macular degeneration (AMD), in which visual impairment is caused by progressive loss of RPE cells. In contrast to mammals, zebrafish possess the ability to intrinsically regenerate a functional RPE layer after severe injury. The molecular underpinnings of this regenerative process remain largely unknown yet hold tremendous potential for developing treatment strategies to stimulate endogenous regeneration in the human eye. In this study, we demonstrate that the mTOR pathway is activated in RPE cells post-genetic ablation. Pharmacological and genetic inhibition of mTOR activity impaired RPE regeneration, while mTOR activation enhanced RPE recovery post-injury, demonstrating that mTOR activity is essential for RPE regeneration in zebrafish. RNA-seq of RPE isolated from mTOR-inhibited larvae identified a number of genes and pathways dependent on mTOR activity at early and late stages of regeneration; amongst these were components of the immune system, which is emerging as a key regulator of regenerative responses across various tissue and model systems. Our results identify crosstalk between macrophages/microglia and the RPE, wherein mTOR activity is required for recruitment of macrophages/microglia to the RPE injury site. Macrophages/microglia then reinforce mTOR activity in regenerating RPE cells. Interestingly, the function of macrophages/microglia in maintaining mTOR activity in the RPE appeared to be inflammation-independent. Taken together, these data identify mTOR activity as a key regulator of RPE regeneration and link the mTOR pathway to immune responses in facilitating RPE regeneration. |
| first_indexed | 2024-04-10T09:30:51Z |
| format | Article |
| id | doaj.art-4ff72f4de9d74fe38249630f8e4489f1 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-10T09:30:51Z |
| publishDate | 2022-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-4ff72f4de9d74fe38249630f8e4489f12023-02-19T05:31:21ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042022-03-01183e100962810.1371/journal.pgen.1009628mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish.Fangfang LuLyndsay L LeachJeffrey M GrossThe retinal pigment epithelium (RPE) plays numerous critical roles in maintaining vision and this is underscored by the prevalence of degenerative blinding diseases like age-related macular degeneration (AMD), in which visual impairment is caused by progressive loss of RPE cells. In contrast to mammals, zebrafish possess the ability to intrinsically regenerate a functional RPE layer after severe injury. The molecular underpinnings of this regenerative process remain largely unknown yet hold tremendous potential for developing treatment strategies to stimulate endogenous regeneration in the human eye. In this study, we demonstrate that the mTOR pathway is activated in RPE cells post-genetic ablation. Pharmacological and genetic inhibition of mTOR activity impaired RPE regeneration, while mTOR activation enhanced RPE recovery post-injury, demonstrating that mTOR activity is essential for RPE regeneration in zebrafish. RNA-seq of RPE isolated from mTOR-inhibited larvae identified a number of genes and pathways dependent on mTOR activity at early and late stages of regeneration; amongst these were components of the immune system, which is emerging as a key regulator of regenerative responses across various tissue and model systems. Our results identify crosstalk between macrophages/microglia and the RPE, wherein mTOR activity is required for recruitment of macrophages/microglia to the RPE injury site. Macrophages/microglia then reinforce mTOR activity in regenerating RPE cells. Interestingly, the function of macrophages/microglia in maintaining mTOR activity in the RPE appeared to be inflammation-independent. Taken together, these data identify mTOR activity as a key regulator of RPE regeneration and link the mTOR pathway to immune responses in facilitating RPE regeneration.https://doi.org/10.1371/journal.pgen.1009628 |
| spellingShingle | Fangfang Lu Lyndsay L Leach Jeffrey M Gross mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish. PLoS Genetics |
| title | mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish. |
| title_full | mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish. |
| title_fullStr | mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish. |
| title_full_unstemmed | mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish. |
| title_short | mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish. |
| title_sort | mtor activity is essential for retinal pigment epithelium regeneration in zebrafish |
| url | https://doi.org/10.1371/journal.pgen.1009628 |
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