June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Genetic deficiency of RORα leads to retinal bipolar cell dysfunction in aging mice
Author Affiliations & Notes
  • Kiran Bora
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Chi-Hsiu Liu
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Felix Yemanyi
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Alexandra K. Blomfield
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Meenakshi Maurya
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Ye Sun
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • James Akula
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Jing Chen
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Kiran Bora None; Chi-Hsiu Liu None; Felix Yemanyi None; Alexandra Blomfield None; Meenakshi Maurya None; Ye Sun None; James Akula None; Jing Chen None
  • Footnotes
    Support  NIH/NEI R01 grant EY024963, NIH/NEI R01 grant EY028100 and NIH/NEI R01 grant EY031765
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 4112 – F0349. doi:
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    • Get Citation

      Kiran Bora, Chi-Hsiu Liu, Felix Yemanyi, Alexandra K. Blomfield, Meenakshi Maurya, Ye Sun, James Akula, Jing Chen; Genetic deficiency of RORα leads to retinal bipolar cell dysfunction in aging mice. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4112 – F0349.

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

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Abstract

Purpose : Retinoic acid receptor-related orphan receptor alpha (RORα) is a lipid-sensing nuclear receptor and transcription factor expressed in many retinal cell types including photoreceptors, ganglion cells and bipolar cells. It plays a crucial role in regulating expression of target genes involved in diverse physiological processes in the eye, such as those in lens and photoreceptor development. Genetic variations of RORα have been linked to development of age-related macular degeneration. In this study, we investigated the role of RORα in retinal bipolar cell function during aging using mice with spontaneous RORα deletion mutation (RORαsg/sg).

Methods : RORαsg/sg and age-matched wild-type (WT) mice were assessed at various time points during aging for functional and phenotypical analysis. The distribution of RORα in retina was analyzed using single cell RNA sequencing (scRNA seq) database and its localization was monitored by immunohistochemistry, along with evaluation of changes in bipolar cell morphology using PKCα, a rod bipolar cell selective marker. Further, visual function was assessed by scotopic full-field electroretinography (ERG), and retinal expression of genes involved in signal transmission through bipolar cells was determined in RORαsg/sg and WT mice.

Results : RORα expression was found in retinal bipolar cells in scRNA seq analysis and its localization was confirmed in retinal sections. Compared with WT, RORαsg/sg mice showed substantial impairment of visual function with significant attenuation (P=0.0002) of b-wave ERG amplitude at 5 month, with greater reduction (P=0.04) at 12 month, suggestive of bipolar cell dysfunction. However, ERG a-waves, which originate in photoreceptors, were comparatively normal. RORasg/sg mice revealed significant degeneration and progressive loss of bipolar cells upon aging, with notable loss of rod bipolar cells at 5 months followed by more conspicuous loss and severely disrupted morphology upon aging (9 months and >12 months old), with respect to WT. Furthermore, RORasg/sg retinal tissues revealed significant dysregulation of genes involved in glutamate and calcium signaling.

Conclusions : These findings suggest that RORα deficiency results in progressive, age-related rod bipolar cell degeneration with associated visual dysfunction, indicating a crucial role of RORα in regulating rod bipolar cell integrity and function in aging eyes.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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