Knockout of Nr2e3 prevents rod photoreceptor differentiation and leads to selective L-/M-cone photoreceptor degeneration in zebrafish

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Xie, Shanglun¹  Han, Shanshan¹  Qu, Zhen¹  Liu, Fei¹  Li, Jingzhen¹  Yu, Shanshan¹  Reilly, James²  Tu, Jiayi¹  Liu, Xiliang¹  Lu, Zhaojing¹  Hu, Xuebin¹  Yimer, Tinsae Assefa¹  Qin, Yayun¹  Huang, Yuwen¹  Lv, Yuexia¹  Jiang, Tao¹  Shu, Xinhua²  Tang, Zhaohui¹  Jia, Haibo¹  Wong, Fulton³  Liu, Mugen¹ 

[1] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Minist Educ, Key Lab Mol Biophys, Wuhan 430074, Hubei, Peoples R China

[2] Glasgow Caledonian Univ, Dept Life Sci, Glasgow G4 0BA, Lanark, Scotland

[3] Duke Univ, Sch Med, Dept Ophthalmol, Durham, NC 27710 USA

关键词: Nr2e3;    CRISPR;    Zebrafish;    Photoreceptor;    Differentiation;    Degeneration;   

DOI  :  10.1016/j.bbadis.2019.01.022

来源: Elsevier

【 摘 要 】

Mutations in the photoreceptor cell-specific nuclear receptor gene Nr2e3 increased the number of S-cone photoreceptors in human and murine retinas and led to retinal degeneration that involved photoreceptor and non photoreceptor cells. The mechanisms underlying these complex phenotypes remain unclear. In the hope of understanding the precise role of Nr2e3 in photoreceptor cell fate determination and differentiation, we generated a line of Nr2e3 knockout zebrafish using CRISPR technology. In these Nr2e3-null animals, rod precursors undergo terminal mitoses but fail to differentiate as rods. Rod-specific genes are not expressed and the outer segment (OS) fails to form. Formation and differentiation of cone photoreceptors is normal. Specifically, there is no increase in the number of UV-cone or S-cone photoreceptors. Laminated retinal structure is maintained. After normal development, L-/M-cones selectively degenerate, with progressive shortening of OS that starts at age 1 month. The amount of cone phototransduction proteins is concomitantly reduced, whereas UV- and S-cones have normal OS lengths even at age 10 months. In vitro studies show Nr2e3 synergizes with Crx and Nrl to enhance rhodopsin gene expression. Nr2e3 does not affect cone opsin expression. Our results extend the knowledge of Nr2e3's roles and have specific implications for the interpretation of the phenotypes observed in human and murine retinas. Furthermore, our model may offer new opportunities in finding treatments for enhanced S-cone syndrome (ESCS) and other retinal degenerative diseases.

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