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. 2024 Mar 19;16(4):805–822. doi: 10.1038/s44321-024-00053-x

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.

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U-ExM revealed the efficacy of the gene therapy treatment 3 months post injection. (A) Localization of proteins composing the CC in the WT retina. (B) Injection of FCBR1-F0.4-HS produced a marked rescue of the ONL (compared with (E)), but also ectopic expression of FAM161A and POC5 (see yellow arrows). Note the small size of the CEP290-positive CC (yellow arrow). The LCA5 labeling is discrete (yellow arrow), whereas the IFT81 labeling is correct (white arrows). (C) FCBR1-F0.4-HL also protected the retina and produced a correct localization of FAM161A at the CC and OPL levels as previously described (white arrows), but FAM161A labeling appeared too long in comparison to the WT CC (A, F). LCA5 is imperfectly expressed in the CC (orange arrow), but IFT81 appeared at the correct localization (white arrows). (D) The co-administration of the two FAM161A isoforms led to ONL protection, discrete FAM161A expression in the CC and OPL (white arrows), and correct localization of FAM161A, POC5, CEP290, LCA5 as well as IFT81 (white arrows). (F) Quantification of FAM161A- and POC5-positive CC lengths. Note that the CC is longer for the IRBP-GRK1-HS + IRBP-GRK1-HL group (P < 0.0001) and shorter for the FCBR1-F0.4-HS group (P < 0.0001) compared to the WT CC length determined by POC5 staining (mean and SD represented as horizontal plain and dotted line, respectively). One-way ANOVA Kruskal–Wallis test followed by Dunn’s test for multiple comparisons of all groups to the control WT group; *P < 0.05; ****P < 0.0001. (A) Low magnification FAM161A labelings from flatmount retina are shown, whereas all other panels are stainings on cryosection. Scale bars: 20 μm and 1 μm for low and high magnification, respectively. HS human short isoform, HL human long isoform, ONL outer nuclear layer, CC connecting cilium, OPL outer plexiform layer. White arrows: correct labeling; orange arrows: modified labeling. Data information: Results in (A–E) are representative of two sections (A, C–E) or three sections (B) from one eye for each group. Results in (F) using FAM161A labeling were obtained from measurements of 22 connecting cilia for IRBP-GRK1-HS + HL, 21 for FCBR1-F0.4-HS, 24 for FCBR1-F0.4-HL, and 27 for FCBR1-F0.4-HS + HL. Results in (F) using POC5 labeling were obtained from measurements of 27 connecting cilia for IRBP-GRK1-HS + HL, 16 for FCBR1-F0.4-HS, 28 for FCBR1-F0.4-HL, 24 for FCBR1-F0.4-HS + HL and 70 for WT. Source data are available online for this figure.