Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish
Abstract Mutations in TUB-like protein 1 (TULP1) are associated with severe early-onset retinal degeneration in humans. However, the pathogenesis remains largely unknown. There are two homologous genes of TULP1 in zebrafish, namely tulp1a and tulp1b. Here, we generated the single knockout (tulp1a −/...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-11-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05372-w |
| _version_ | 1811219397249859584 |
|---|---|
| author | Danna Jia Pan Gao Yuexia Lv Yuwen Huang James Reilly Kui Sun Yunqiao Han Hualei Hu Xiang Chen Zuxiao Zhang Pei Li Jiong Luo Xinhua Shu Zhaohui Tang Fei Liu Mugen Liu Xiang Ren |
| author_facet | Danna Jia Pan Gao Yuexia Lv Yuwen Huang James Reilly Kui Sun Yunqiao Han Hualei Hu Xiang Chen Zuxiao Zhang Pei Li Jiong Luo Xinhua Shu Zhaohui Tang Fei Liu Mugen Liu Xiang Ren |
| author_sort | Danna Jia |
| collection | DOAJ |
| description | Abstract Mutations in TUB-like protein 1 (TULP1) are associated with severe early-onset retinal degeneration in humans. However, the pathogenesis remains largely unknown. There are two homologous genes of TULP1 in zebrafish, namely tulp1a and tulp1b. Here, we generated the single knockout (tulp1a −/− and tulp1b −/− ) and double knockout (tulp1-dKO) models in zebrafish. Knockout of tulp1a resulted in the mislocalization of UV cone opsins and the degeneration of UV cones specifically, while knockout of tulp1b resulted in mislocalization of rod opsins and rod-cone degeneration. In the tulp1-dKO zebrafish, mislocalization of opsins was present in all types of photoreceptors, and severe degeneration was observed at a very early age, mimicking the clinical manifestations of TULP1 patients. Photoreceptor cilium length was significantly reduced in the tulp1-dKO retinas. RNA-seq analysis showed that the expression of tektin2 (tekt2), a ciliary and flagellar microtubule structural component, was downregulated in the tulp1-dKO zebrafish. Dual-luciferase reporter assay suggested that Tulp1a and Tulp1b transcriptionally activate the promoter of tekt2. In addition, ferroptosis might be activated in the tulp1-dKO zebrafish, as suggested by the up-regulation of genes related to the ferroptosis pathway, the shrinkage of mitochondria, reduction or disappearance of mitochondria cristae, and the iron and lipid droplet deposition in the retina of tulp1-dKO zebrafish. In conclusion, our study establishes an appropriate zebrafish model for TULP1-associated retinal degeneration and proposes that loss of TULP1 causes defects in cilia structure and opsin trafficking through the downregulation of tekt2, which further increases the death of photoreceptors via ferroptosis. These findings offer insight into the pathogenesis and clinical treatment of early-onset retinal degeneration. |
| first_indexed | 2024-04-12T07:26:20Z |
| format | Article |
| id | doaj.art-a4488838773d40f3b42c175e4b6f0088 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T07:26:20Z |
| publishDate | 2022-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-a4488838773d40f3b42c175e4b6f00882022-12-22T03:42:12ZengNature Publishing GroupCell Death and Disease2041-48892022-11-01131111110.1038/s41419-022-05372-wTulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafishDanna Jia0Pan Gao1Yuexia Lv2Yuwen Huang3James Reilly4Kui Sun5Yunqiao Han6Hualei Hu7Xiang Chen8Zuxiao Zhang9Pei Li10Jiong Luo11Xinhua Shu12Zhaohui Tang13Fei Liu14Mugen Liu15Xiang Ren16Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyPrenatal Diagnosis Center, The Third Affiliated Hospital of Zhengzhou UniversityKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyDepartment of Biological and Biomedical Sciences, Glasgow Caledonian UniversityKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyDepartment of Biological and Biomedical Sciences, Glasgow Caledonian UniversityKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, The Innovative Academy of Seed Design, Hubei Hongshan Laboratory, Chinese Academy of SciencesKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyKey Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and TechnologyAbstract Mutations in TUB-like protein 1 (TULP1) are associated with severe early-onset retinal degeneration in humans. However, the pathogenesis remains largely unknown. There are two homologous genes of TULP1 in zebrafish, namely tulp1a and tulp1b. Here, we generated the single knockout (tulp1a −/− and tulp1b −/− ) and double knockout (tulp1-dKO) models in zebrafish. Knockout of tulp1a resulted in the mislocalization of UV cone opsins and the degeneration of UV cones specifically, while knockout of tulp1b resulted in mislocalization of rod opsins and rod-cone degeneration. In the tulp1-dKO zebrafish, mislocalization of opsins was present in all types of photoreceptors, and severe degeneration was observed at a very early age, mimicking the clinical manifestations of TULP1 patients. Photoreceptor cilium length was significantly reduced in the tulp1-dKO retinas. RNA-seq analysis showed that the expression of tektin2 (tekt2), a ciliary and flagellar microtubule structural component, was downregulated in the tulp1-dKO zebrafish. Dual-luciferase reporter assay suggested that Tulp1a and Tulp1b transcriptionally activate the promoter of tekt2. In addition, ferroptosis might be activated in the tulp1-dKO zebrafish, as suggested by the up-regulation of genes related to the ferroptosis pathway, the shrinkage of mitochondria, reduction or disappearance of mitochondria cristae, and the iron and lipid droplet deposition in the retina of tulp1-dKO zebrafish. In conclusion, our study establishes an appropriate zebrafish model for TULP1-associated retinal degeneration and proposes that loss of TULP1 causes defects in cilia structure and opsin trafficking through the downregulation of tekt2, which further increases the death of photoreceptors via ferroptosis. These findings offer insight into the pathogenesis and clinical treatment of early-onset retinal degeneration.https://doi.org/10.1038/s41419-022-05372-w |
| spellingShingle | Danna Jia Pan Gao Yuexia Lv Yuwen Huang James Reilly Kui Sun Yunqiao Han Hualei Hu Xiang Chen Zuxiao Zhang Pei Li Jiong Luo Xinhua Shu Zhaohui Tang Fei Liu Mugen Liu Xiang Ren Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish Cell Death and Disease |
| title | Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish |
| title_full | Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish |
| title_fullStr | Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish |
| title_full_unstemmed | Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish |
| title_short | Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish |
| title_sort | tulp1 deficiency causes early onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish |
| url | https://doi.org/10.1038/s41419-022-05372-w |
| work_keys_str_mv | AT dannajia tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT pangao tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT yuexialv tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT yuwenhuang tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT jamesreilly tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT kuisun tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT yunqiaohan tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT hualeihu tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT xiangchen tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT zuxiaozhang tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT peili tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT jiongluo tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT xinhuashu tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT zhaohuitang tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT feiliu tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT mugenliu tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish AT xiangren tulp1deficiencycausesearlyonsetretinaldegenerationthroughaffectingciliogenesisandactivatingferroptosisinzebrafish |