Deletion of the Impg2 gene causes the degeneration of rod and cone cells in mice
| العنوان: | Deletion of the Impg2 gene causes the degeneration of rod and cone cells in mice |
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| المؤلفون: | Huijuan Xu, Xianjun Zhu, Li Jiang, Junkai Tan, Lin Zhang, Zhilin Jiang, Li Gan, Chao Qu, Shanshan Zhang, Wenjing Liu, Wanli Tian, Xuyang Liu, Yeming Yang, Kuanxiang Sun |
| المصدر: | Human Molecular Genetics. 29:1624-1634 |
| بيانات النشر: | Oxford University Press (OUP), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Rhodopsin, genetic structures, Protein Disulfide-Isomerases, Interphotoreceptor matrix, Biology, Retina, Mice, 03 medical and health sciences, 0302 clinical medicine, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, Autophagy, Genetics, medicine, Animals, Humans, Protein disulfide-isomerase, Endoplasmic Reticulum Chaperone BiP, Molecular Biology, Heat-Shock Proteins, Genetics (clinical), 030304 developmental biology, Mice, Knockout, 0303 health sciences, Cell Death, Endoplasmic reticulum, Retinal Degeneration, General Medicine, Endoplasmic Reticulum Stress, medicine.disease, eye diseases, Cone cell, Cell biology, medicine.anatomical_structure, Retinal Cone Photoreceptor Cells, Unfolded protein response, Proteoglycans, sense organs, CRISPR-Cas Systems, Transcription Factor CHOP, 030217 neurology & neurosurgery |
| الوصف: | Variants in interphotoreceptor matrix proteoglycans (IMPG2) have been reported in retinitis pigmentosa (RP) and vitelliform macular dystrophy (VMD) patients. However, the underlying molecular mechanisms remain elusive due to a lack of suitable disease models. We developed two independent Impg2 knockout (KO) mouse models using the CRISPR/Cas9 technique to assess the in vivo functions of Impg2 in the retina. Impg2 ablation in mice recapitulated the RP phenotypes of patients, including an attenuated electroretinogram (ERG) response and the progressive degeneration of photoreceptors. The histopathological examination of Impg2-KO mice revealed irregularly arranged rod cells and mislocalized rhodopsin protein in the inner segment at 6 months of age. In addition to the pathological changes in rod cells, cone cells were also affected in KO retinas. KO retinas exhibited progressive cone cell death and impaired cone cell elongation. Further immunoblotting analysis revealed increased levels of endoplasmic reticulum (ER) stress-related proteins, including C/EBP homologous protein (CHOP), immunoglobulin heavy-chain-binding protein (BIP) and protein disulfide isomerase (PDI), in Impg2-KO mouse retinas. Increased gliosis and apoptotic cell death were also observed in the KO retinas. As autophagy is closely associated with ER stress, we then checked whether autophagy was disturbed in Impg2-KO mouse retinas. The results showed that autophagy was impaired in KO retinas, as revealed by the increased accumulation of SQSTM1 and other proteins involved in autophagy. Our results demonstrate the essential roles of Impg2 in the retina, and this study provides novel models for mechanistic investigations and development of therapies for RP caused by IMPG2 mutations. |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e3265c5db1a29edc4dca40979c87c2adTest https://doi.org/10.1093/hmg/ddaa062Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e3265c5db1a29edc4dca40979c87c2ad |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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