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

Shanglun Xie, Shanshan Han, Zhen Qu, Fei Liu, Jingzhen Li, Shanshan Yu, James Reilly, Jiayi Tu, Xiliang Liu, Xuebin Hu, Tinsae Assefa Yimer, Yayun Qin, Yuwen Huang, Yuexia Lv, Tao Jiang, Xinhua Shu, Zhaohui Tang, Mugen Liu

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Abstract

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 nonphotoreceptor 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.
Original languageEnglish
Pages (from-to)1273-1283
Number of pages11
JournalBiochimica et Biophysica Acta (BBA)
Volume1865
Issue number6
Early online date23 Jan 2019
DOIs
Publication statusPublished - 1 Jun 2019

Keywords

  • photoreceptor
  • zebrafish
  • retinal degeneration

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