Vitamin A (all-trans retinol) plays critical roles in mammalian development and vision. Since vitamin A is food-derived, tissue-specific uptake and storage mechanism are needed. In the eye, uptake of RBP4-retinol is mediated by the receptor Stra6, whereas the receptor mediating RBP4 binding and retinol transport into the liver has just recently been discovered. Here we examined the role of zebrafish retinol binding protein receptor 2 (Rbpr2) for RBP4-retinol uptake in developing embryos, using eye development and vision as sensitive readouts. In cultured cells, Rbpr2 localized to membranes and promoted RBP4-retinol uptake. In larvae, Rbpr2 expression was detected in developing intestinal enterocytes and liver hepatocytes. Two rbpr2 mutant zebrafish lines, each resulting in Rbpr2 deficiency, exhibit a small eye defect, and systemic malformations including hydrocephaly and cardiac edema, phenotypes associated with vitamin A deficiency. In the retina, Rbpr2 loss resulted in shorter photoreceptor outer segments, mislocalization and decrease in visual pigments, decreased expression of retinoic acid-responsive genes and photoreceptor cell loss, overall leading to a reduction of visual function. Together, these results demonstrate that Rbpr2-mediated RBP4-retinol uptake in developing liver and intestine is necessary to provide sufficient substrate for ocular retinoid production required for photoreceptor cell maintenance and visual function.
|Original language||English (US)|
|State||Published - Dec 1 2017|
Bibliographical noteFunding Information:
This work was supported by grants from NEI EY025034 (G.P.L) and R01EY024581 (B. Rohrer), Knights Templar Eye Foundation Career Starter Grant (G.P.L), Knights Templar Eye Foundation Career Starter Renewal Grant (G.P.L), Medical University of South Carolina (MUSC) start-up funds (G.P.L), VA I01BX003050 (B. Rohrer) and RX000444 SmartState Chair Endowment (B. Rohrer). We thank Drs. Johannes von Lintig and Marcin Golczak (Department of Pharmacology, Case Western Reserve University, Cleveland, OH) for assistance with expression and purification of human RBP4 protein. We also thank Drs. Brian Perkins, Joe Fogerty and Lauren Daniele (Cole Eye Institute, Cleveland Clinic, Cleveland, OH) for assistance with establishing zebrafish experiments and zebrafish OKR readings.
© 2017 The Author(s).