2022 Annual Meeting and Alumni Reunion
Category : Basic and Translational Research Candidate : Kiran Bora Poster #: B4
Genetic Deficiency of RORα Leads to Retinal Bipolar Cell Dysfunction in Aging Mice
Kiran Bora †, Chi-Hsiu Liu †, Felix Yemanyi , Alexandra K . Blomfield , Meenakshi Maurya , Ye Sun , James D . Akula , Jing Chen *
Purpose : Retinoic acid receptor-related orphan receptor alpha ( RORα ) is a lipid-sensing nuclear receptor 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 alterations 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 . RORasg / 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 dysfunction . However , ERG a-waves 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 ( 12 months ) 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 .