New insights and changing paradigms in the regulation of vitamin A metabolism in development

Abstract

Vitamin A and its active metabolite retinoic acid are essential for embryonic development and adult homeostasis. Surprisingly, excess or deficiency of vitamin A and retinoic acid can cause similar developmental defects. Therefore, strict feedback and other mechanisms exist to regulate the levels of retinoic acid within a narrow physiological range. The oxidation of vitamin A to retinal has recently been established as a critical nodal point in the synthesis of retinoic acid, and over the past decade, RDH10 and DHRS3 have emerged as the predominant enzymes that regulate this reversible reaction. Together they form a codependent complex that facilitates negative feedback maintenance of retinoic acid levels and thus guard against the effects of dysregulated vitamin A metabolism and retinoic acid synthesis. This review focuses on advances in our understanding of the roles of Rdh10 and Dhrs3 and their impact on development and disease. WIREs Dev Biol 2017, 6:e264. doi: 10.1002/wdev.264 For further resources related to this article, please visit the WIREs website.

FIGURE 1

Preformed vitamin A is taken up from the intestinal lumen by enterocytes and transported via the blood supply as all-trans-retinol to its various target tissues. Large stores of vitamin A are kept in hepatic stellate cells of the liver by esterification of all-trans-retinol to retinyl esters. Mobilization of these stores is carried out by hydrolysis of retinyl esters back to all-trans-retinol where it is then transported by the blood supply through binding to RBP4. At target tissues, the RBP receptor, STRA6, allows for the import of retinol associated with RBP4. Once inside the cell, retinol associates with the RDH10/DHRS3 complex in the first reversible step of vitamin A metabolism to be oxidized to all-trans-retinaldehyde by RDH10. All-trans-retinaldehyde can then be reduced back to all-trans-retinol by DHRS3, or it may be further oxidized by the ALDH genes (ALDH1A1–ALDH1A3) to form ATRA. ATRA then serves as a ligand for one of three isotypes of the RARs which form a heterodimer with RXR. The RAR–RXRs associate with retinoic acid response elements (RARE) within the promoters of target genes and can induce both transcriptional activation and silencing.

FIGURE 2

(a–p) Lateral and dorsal views of E9.5, E10.5, E12.5, and E14.5 control RARE-LacZ, Rdh10^trex/trex; RARE-LacZ, and Dhrs3^−/−;RARE-LacZ embryos illustrating diminished retinoic acid signaling in the craniofacial and trunk regions of Rdh10^trex/trex embryos and expanded regions of signaling in the frontonasal region and tail of Dhrs3^−/− embryos. (q) Lateral view of LacZ expression in a bisected E14.5 Rdh10^bgeo/+ embryo revealing RDH10 activity in the upper and lower lip, nasal epithelium, neural tube, heart, gut, and interdigital zone of the limbs. (r) Lateral view of an E14.5 embryo section immunostained with anti-DHRS3 (red) and DAPI (blue) illustrating DHRS3 activity in the neural tube, heart, liver, kidney, and nasal epithelium; g, gut; h, heart; id, interdigital zone of the limbs; ki, kidney; li, liver; ul, upper lip; ll, lower lip; nt, neural tube; ne, nasal epithelium. Panels (g)–(i) were adapted from Ref .