June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
CRALBP is required for the function of the mammalian retina visual cycle and normal M-cone vision
Author Affiliations & Notes
  • Yunlu Xue
    Washington University School of Medicine, St. Louis, MO
  • Susan Shen
    Washington University School of Medicine, St. Louis, MO
  • Jonathan Jui
    UC Berkeley, Berkeley, CA
  • Alan C Rupp
    Johns Hopkins University, Baltimore, MD
  • Leah Byrne
    UC Berkeley, Berkeley, CA
  • Samer Hattar
    Johns Hopkins University, Baltimore, MD
  • John Gerard Flannery
    UC Berkeley, Berkeley, CA
  • Joseph C Corbo
    Washington University School of Medicine, St. Louis, MO
  • Vladimir J Kefalov
    Washington University School of Medicine, St. Louis, MO
  • Footnotes
    Commercial Relationships Yunlu Xue, None; Susan Shen, None; Jonathan Jui, None; Alan Rupp, None; Leah Byrne, None; Samer Hattar, None; John Flannery, None; Joseph Corbo, None; Vladimir Kefalov, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 1703. doi:
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      Yunlu Xue, Susan Shen, Jonathan Jui, Alan C Rupp, Leah Byrne, Samer Hattar, John Gerard Flannery, Joseph C Corbo, Vladimir J Kefalov; CRALBP is required for the function of the mammalian retina visual cycle and normal M-cone vision. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1703.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Efficient regeneration of visual pigments is required for the function of mammalian photoreceptors. Cellular retinaldehyde-binding protein (CRALBP), a carrier for 11-cis retinoids, is known to potentiate the visual cycle in the retinal pigmented epithelium (RPE) and promote rod photoreceptor dark adaptation. However, it is not known whether CRALPB modulation of the RPE visual cycle affects the function of mammalian cone photoreceptors. The function of CRALBP in retinal Müller cells, which have been proposed to mediate an independent, cone photoreceptor-specific visual cycle, is also unknown. Therefore, we sought to determine the role of CRALBP in modulating the RPE and Müller cell visual cycles and in supporting mammalian cone function.

Methods: Rlbp1-/- (CRALBP-deficient) mice were crossed with Gnat1-/- (transducin α-subunit knockout) mice to facilitate cone recordings. All mice were dark adapted overnight before recordings. We used optomotor test, in vivo ERG, and transretinal recordings to determine how the deletion of CRALBP affects M-cone function. We also used immunohistochemistry to identify the role of CRALBP in supporting M-cone morphology and survival. In effort to rescue M-cone function, Rlbp1-/- mice were treated with exogenous chromophore, dark-rearing, and adeno-associated virus (AAV) based gene therapy.

Results: We demonstrate that the deletion of CRALBP in mice impairs M-cone survival and opsin localization as well as M-cone-driven visual behavior, light responses, and dark adaptation. Dark rearing of CRALBP knockout mice prevented the deterioration of M-cone function but did not rescue M-cone dark adaptation. Restoring CRALBP expression specifically in the Müller cells of knockout mice rescued the retina visual cycle and cone sensitivity, whereas the expression of CRALBP specifically in RPE cells did not. The expression of CRALBP in either Müller or RPE cells was sufficient to partially rescue cone dark adaptation in vivo.

Conclusions: These results provide functional validation of the retina visual cycle and demonstrate that CRALBP is a key component of this pathway. Our findings reveal that the Müller cell visual cycle is required for maintaining normal cone function and highlight the distinct roles of the RPE and retina visual cycles in cone dark adaptation, providing mechanistic insights to the cone photoreceptor-mediated vision loss caused by human CRALBP mutations.

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