CRALBP supports the mammalian retinal visual cycle and cone vision
Yunlu Xue, … , Joseph C. Corbo, Vladimir J. Kefalov
Yunlu Xue, … , Joseph C. Corbo, Vladimir J. Kefalov
Published January 20, 2015
Citation Information: J Clin Invest. 2015;125(2):727-738. https://doi.org/10.1172/JCI79651.
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Research Article Ophthalmology

CRALBP supports the mammalian retinal visual cycle and cone vision

Abstract

Mutations in the cellular retinaldehyde–binding protein (CRALBP, encoded by RLBP1) can lead to severe cone photoreceptor–mediated vision loss in patients. It is not known how CRALBP supports cone function or how altered CRALBP leads to cone dysfunction. Here, we determined that deletion of Rlbp1 in mice impairs the retinal visual cycle. Mice lacking CRALBP exhibited M-opsin mislocalization, M-cone loss, and impaired cone-driven visual behavior and light responses. Additionally, M-cone dark adaptation was largely suppressed in CRALBP-deficient animals. While rearing CRALBP-deficient mice in the dark prevented the deterioration of cone function, it did not rescue cone dark adaptation. Adeno-associated virus–mediated restoration of CRALBP expression specifically in Müller cells, but not retinal pigment epithelial (RPE) cells, rescued the retinal visual cycle and M-cone sensitivity in knockout mice. Our results identify Müller cell CRALBP as a key component of the retinal visual cycle and demonstrate that this pathway is important for maintaining normal cone–driven vision and accelerating cone dark adaptation.

Authors

Yunlu Xue, Susan Q. Shen, Jonathan Jui, Alan C. Rupp, Leah C. Byrne, Samer Hattar, John G. Flannery, Joseph C. Corbo, Vladimir J. Kefalov

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Figure 4

Dark rearing, but not acute treatment with exogenous chromophore, rescues CRALBP-deficient cone sensitivity.

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Dark rearing, but not acute treatment with exogenous chromophore, rescue...
(A) Normalized in vivo ERG cone b-wave intensity-response curves for untreated control (replotted from Figure 2B inset) and 9-cis retinal–treated (n = 6) Rlbp1–/– mice. (B) Normalized transretinal cone intensity-response curves for control (black, n = 6) and Rlbp1–/– (red, n = 6) retinae in control solution (filled symbols; replotted from Figure 3B inset) and after treatment with exogenous 11-cis retinal (open symbols, n = 6). 9cRal, 9-cis retinal; 11cRal, 11-cis retinal. (C) Cone b-wave intensity-response curves from in vivo ERG recordings of control mice raised in cyclic light (black squares, n = 14) or in darkness (white squares, n = 10). (D) Cone b-wave intensity-response curves from in vivo ERG recordings of control (black squares; replotted from Figure 1B) and Rlbp1–/– mice raised in cyclic light (red filled circles; replotted from Figure 1B) and Rlbp1–/– mice raised in darkness (open red circles, n = 10). Insets in C and D show the corresponding normalized intensity-response curves. (E) Normalized cone b-wave sensitivity (b-wave Sf / b-wave SfDA) from in vivo ERG recordings during dark adaptation following 90% pigment bleaching at t = 0 for control (black squares) and Rlbp1–/– mice raised in cyclic light (filled red circles; replotted from Figure 4A) and for Rlbp1–/– mice raised in darkness (open red circles, n = 10). Results represent the mean ± SEM.