期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 47, 页码 24465-24474出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.738658
关键词
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资金
- Japan Science and Technology Agency (JST)
- Japan Society for the Promotion of Science (JSPS) [JP25113519, JP15H04669, JP25293070, JP16K08583, JP15K18955]
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [12024046]
- Takeda Science Foundation
- Uehara Memorial Foundation
- Novartis Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Naito Foundation
- Send Life Science Foundation
- Kato Memorial Bioscience Foundation
- Daiichi-Sankyo Foundation of Life Science
- Suzuken Memorial Foundation
- Osaka Community Foundation
- NIG Collaborative Research Program [201685]
- National Institutes of Health from the NEI [EY018176]
- MRC [MR/N000714/1] Funding Source: UKRI
- Medical Research Council [MR/N000714/1] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [15H04669, 16K08583] Funding Source: KAKEN
In the retina, aberrant opsin transport from cell bodies to outer segments leads to retinal degenerative diseases such as retinitis pigmentosa. Opsin transport is facilitated by the intra-flagellar transport (LET) system that mediates the bidirectional movement of proteins within cilia. In contrast to functions of the anterograde transport executed by IFT complex B (IFT-B), the precise functions of the retrograde transport mediated by LET complex A (IFT-A) have not been well studied in photoreceptor cilia. Here, we analyzed developing zebrafish larvae carrying a null mutation in ift122 encoding a component of IFT-A. ift122 mutant larvae show unexpectedly mild phenotypes, compared with those of mutants defective in IFT-B. ift122 mutants exhibit a slow onset of progressive photoreceptor degeneration mainly after 7 days post-fertilization. ift122 mutant larvae also develop cystic kidney but not curly body, both of which are typically observed in various ciliary mutants. ift122 mutants display a loss of cilia in the inner ear hair cells and nasal pit epithelia. Loss of ift122 causes disorganization of outer segment discs. Ectopic accumulation of an IFT-B component, ift88, is observed in the ift122 mutant photoreceptor cilia. In addition, pulse chase experiments using GFP-opsin fusion proteins revealed that ift122 is required for the efficient transport of opsin and the distal elongation of outer segments. These results show that IFT-A is essential for the efficient transport of outer segment proteins, including opsin, and for the survival of retinal photo-receptor cells, rendering the ift122 mutant a unique model for human retinal degenerative diseases.
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