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GLENN LOBO, Elisabeth obert, Altaf A Kondkar, Ashish Solanki, Wayne Fitzgibbon, Deepak Nihalani, Baerbel Rohrer; Mice lacking the Vitamin A transporter RBPR2 show decreased Ocular Retinoid Content and Photoreceptor Phenotypes. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4010.
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© ARVO (1962-2015); The Authors (2016-present)
Transport of dietary vitamin A/all-trans retinol/ROL to peripheral tissues, including the eyes via the circulation, is mediated by the plasma retinol-binding protein (RBP4). STRA6, the only known membrane receptor for cellular RBP4-ROL uptake is expressed in the RPE of the eye, but not in systemic tissues involved in dietary vitamin A uptake, transport and storage. Here, using a mammalian model we investigated the hypothesis that the recently identified retinol binding protein receptor 2 (RBPR2) has high affinity binding for RBP4 and this physical interaction is critical for systemic ROL uptake and transport to the eye for vision.
RBPR2 binding to its ligand RBP4 was performed using computational analysis. Co-immunoprecipitation and sub-cellular fractionation assays were used to determine the functionality of RBP4 binding residues on RBPR2. An rbpr2-/- null mouse line was generated and maintained on different vitamin A diets. Retinal morphological and electron microscopy studies were performed on rbpr2-/- mice to evaluate loss of RBPR2 on ocular retinoid content and retinal pathology. ERG analysis was performed to evaluate visual function in rbpr2-/- and control mice.
Modeling and docking studies confirmed conserved RBP4 binding residues in mouse RBPR2. Immunohistochemical and confocal analysis revealed that Rbpr2 mutants affecting the RBP4 binding sites showed normal membrane expression patterns, but had reduced vitamin A uptake capabilities. Rbpr2-/- mice maintained on vitamin A sufficient diets, showed only reduced ocular retinoid content, but rbpr2-/- mice on low vitamin A diets showed both reduced ocular retinoid content and shorter photoreceptor outer segments. ERG analysis showed loss of visual function in rbpr2-/- mice.
Our studies using RBPR2 null mice established the importance of the vitamin A transporter RBPR2 for the systemic uptake, transport, and serum availability of dietary Vitamin A, which in turn is necessary for proper ocular retinoid homeostasis. In the absence of RBPR2, ocular retinoid content was reduced, and photoreceptor outer segments in rbpr2-/- mice were shorter. The studies reported here demonstrate that the second vitamin A transporter RBPR2 in mice, like STRA6, contains a functional RBP4 binding domain that is critical for the systemic uptake of dietary vitamin A transport to the eye in support of vision.
This is a 2020 ARVO Annual Meeting abstract.
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