DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy
Abstract Epithelial–mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a hallmark of the pathogenesis of proliferative vitreoretinopathy (PVR) that can lead to severe vision loss. Nevertheless, the precise regulatory mechanisms underlying the pathogenesis of PVR remain largely u...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05693-4 |
| _version_ | 1797863410911674368 |
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| author | Xiaoyin Ma Shuxian Han Youjia Liu Yu Chen Pingping Li Xiaoyan Liu Lifu Chang Ying-ao Chen Feng Chen Qiang Hou Ling Hou |
| author_facet | Xiaoyin Ma Shuxian Han Youjia Liu Yu Chen Pingping Li Xiaoyan Liu Lifu Chang Ying-ao Chen Feng Chen Qiang Hou Ling Hou |
| author_sort | Xiaoyin Ma |
| collection | DOAJ |
| description | Abstract Epithelial–mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a hallmark of the pathogenesis of proliferative vitreoretinopathy (PVR) that can lead to severe vision loss. Nevertheless, the precise regulatory mechanisms underlying the pathogenesis of PVR remain largely unknown. Here, we show that the expression of death-associated protein-like 1 (DAPL1) is downregulated in PVR membranes and that DAPL1 deficiency promotes EMT in RPE cells in mice. In fact, adeno-associated virus (AAV)-mediated DAPL1 overexpression in RPE cells of Dapl1-deficient mice inhibited EMT in physiological and retinal-detachment states. In a rabbit model of PVR, ARPE-19 cells overexpressing DAPL1 showed reduced ability to induce experimental PVR, and AAV-mediated DAPL1 delivery attenuated the severity of experimental PVR. Furthermore, a mechanistic study revealed that DAPL1 promotes P21 phosphorylation and its stabilization partially through NFκB (RelA) in RPE cells, whereas the knockdown of P21 led to neutralizing effects on DAPL1-dependent EMT inhibition and enhanced the severity of experimental PVR. These results suggest that DAPL1 acts as a novel suppressor of RPE-EMT and has an important role in antagonizing the pathogenesis of experimental PVR. Hence, this finding has implications for understanding the mechanism of and potential therapeutic applications for PVR. |
| first_indexed | 2024-04-09T22:35:10Z |
| format | Article |
| id | doaj.art-90fc4e475d174a9c867eea1ab6006442 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-09T22:35:10Z |
| publishDate | 2023-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-90fc4e475d174a9c867eea1ab60064422023-03-22T12:32:41ZengNature Publishing GroupCell Death and Disease2041-48892023-02-0114211210.1038/s41419-023-05693-4DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathyXiaoyin Ma0Shuxian Han1Youjia Liu2Yu Chen3Pingping Li4Xiaoyan Liu5Lifu Chang6Ying-ao Chen7Feng Chen8Qiang Hou9Ling Hou10Laboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversityLaboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversityLaboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversityLaboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversityLaboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversityLaboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversityLaboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversityLaboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversitySchool of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversityState Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical UniversityLaboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical UniversityAbstract Epithelial–mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a hallmark of the pathogenesis of proliferative vitreoretinopathy (PVR) that can lead to severe vision loss. Nevertheless, the precise regulatory mechanisms underlying the pathogenesis of PVR remain largely unknown. Here, we show that the expression of death-associated protein-like 1 (DAPL1) is downregulated in PVR membranes and that DAPL1 deficiency promotes EMT in RPE cells in mice. In fact, adeno-associated virus (AAV)-mediated DAPL1 overexpression in RPE cells of Dapl1-deficient mice inhibited EMT in physiological and retinal-detachment states. In a rabbit model of PVR, ARPE-19 cells overexpressing DAPL1 showed reduced ability to induce experimental PVR, and AAV-mediated DAPL1 delivery attenuated the severity of experimental PVR. Furthermore, a mechanistic study revealed that DAPL1 promotes P21 phosphorylation and its stabilization partially through NFκB (RelA) in RPE cells, whereas the knockdown of P21 led to neutralizing effects on DAPL1-dependent EMT inhibition and enhanced the severity of experimental PVR. These results suggest that DAPL1 acts as a novel suppressor of RPE-EMT and has an important role in antagonizing the pathogenesis of experimental PVR. Hence, this finding has implications for understanding the mechanism of and potential therapeutic applications for PVR.https://doi.org/10.1038/s41419-023-05693-4 |
| spellingShingle | Xiaoyin Ma Shuxian Han Youjia Liu Yu Chen Pingping Li Xiaoyan Liu Lifu Chang Ying-ao Chen Feng Chen Qiang Hou Ling Hou DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy Cell Death and Disease |
| title | DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy |
| title_full | DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy |
| title_fullStr | DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy |
| title_full_unstemmed | DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy |
| title_short | DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy |
| title_sort | dapl1 prevents epithelial mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy |
| url | https://doi.org/10.1038/s41419-023-05693-4 |
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