Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

A Functional Binding Domain in the Rbpr2 Receptor is Required for Vitamin A Transport, Ocular Retinoid Homeostasis, and Photoreceptor Cell Survival in Zebrafish

Ashish K. Solanki
ORCID logo ,
Altaf A Kondkar
,
Joseph Fogerty
,
Yanhui Su
,
Seok-hyung Kim
,
Joshua H. Lipschutz
,
Deepak Nihalani
,
Brian D. Perkins
,
Glenn P. Lobo
*
Version 1 : Received: 17 March 2020 / Approved: 19 March 2020 / Online: 19 March 2020 (03:16:19 CET)

A peer-reviewed article of this Preprint also exists.

Solanki, A.K.; Kondkar, A.A.; Fogerty, J.; Su, Y.; Kim, S.-H.; Lipschutz, J.H.; Nihalani, D.; Perkins, B.D.; Lobo, G.P. A Functional Binding Domain in the Rbpr2 Receptor Is Required for Vitamin A Transport, Ocular Retinoid Homeostasis, and Photoreceptor Cell Survival in Zebrafish. Cells 2020, 9, 1099. Solanki, A.K.; Kondkar, A.A.; Fogerty, J.; Su, Y.; Kim, S.-H.; Lipschutz, J.H.; Nihalani, D.; Perkins, B.D.; Lobo, G.P. A Functional Binding Domain in the Rbpr2 Receptor Is Required for Vitamin A Transport, Ocular Retinoid Homeostasis, and Photoreceptor Cell Survival in Zebrafish. Cells 2020, 9, 1099.

Abstract

Dietary vitamin A/all-trans retinol/ROL plays a critical role in human vision. ROL circulates bound to the plasma retinol-binding protein (RBP4) as RBP4-ROL. In the eye, the STRA6 membrane receptor binds to circulatory RBP4 and internalizes ROL. STRA6 is however not expressed in systemic tissues, where there is high-affinity RBP4 binding and ROL uptake. We tested the hypothesis, that the second retinol-binding protein 4 receptor 2 (Rbpr2) which is highly expressed in systemic tissues of zebrafish and mouse, contains a functional RBP4 binding domain, critical for ROL transport. As for STRA6, modeling and docking studies confirmed three conserved RBP4 binding residues in zebrafish Rbpr2. In cell culture studies, disruption of the RBP4 binding residues on Rbpr2 almost completely abolished uptake of exogenous vitamin A. CRISPR generated rbpr2-RBP4 domain zebrafish mutants showed microphthalmia, shorter photoreceptor outer segments, and decreased opsins, that were attributed to impaired ocular retinoid content. Injection of WT-Rbpr2 mRNA into rbpr2 mutant or all-trans retinoic acid treatments rescued the mutant eye phenotypes. In conclusion, zebrafish Rbpr2 contains a putative extracellular RBP4-ROL ligand-binding domain, critical for yolk vitamin A transport to the eye for ocular retinoid production and homeostasis, for photoreceptor cell survival.

Keywords

retinol binding protein 4 receptor 2; RBP4; Rbpr2; STRA6; all-trans retinol transport; photoreceptor cell; vision; retinoids; zebrafish

Subject

Biology and Life Sciences, Cell and Developmental Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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