Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos

Abstract

Embryonic development is orchestrated by a small number of signaling pathways, one of which is the retinoic acid (RA) signaling pathway. Vitamin A is essential for vertebrate embryonic development because it is the molecular precursor of the essential signaling molecule RA. The level and distribution of RA signaling within a developing embryo must be tightly regulated; too much, or too little, or abnormal distribution, all disrupt embryonic development. Precise regulation of RA signaling during embryogenesis is achieved by proteins involved in vitamin A metabolism, retinoid transport, nuclear signaling, and RA catabolism. The reversible first step in conversion of the precursor vitamin A to the active retinoid RA is mediated by retinol dehydrogenase 10 (RDH10) and dehydrogenase/reductase (SDR family) member 3 (DHRS3), two related membrane-bound proteins that functionally activate each other to mediate the interconversion of retinol and retinal. Alcohol dehydrogenase (ADH) enzymes do not contribute to RA production under normal conditions during embryogenesis. Genes involved in vitamin A metabolism and RA catabolism are expressed in tissue-specific patterns and are subject to feedback regulation. Mutations in genes encoding these proteins disrupt morphogenesis of many systems in a developing embryo. Together these observations demonstrate the importance of vitamin A metabolism in regulating RA signaling during embryonic development in vertebrates.

Inverse agonism of retinoic acid receptors directs epiblast cells into the paraxial mesoderm lineage

“…5). With that said, mouse ESCs are commonly maintained in serum free media containing vitamin A, and retinol derivatives stored inside cells (Metzler and Sandell, 2016)may persist over the initial days of differentiation, which may impact early cell fate decisions. Also, work by others suggests vitamin A is a valuable component to the sternness and growth of mouse ESCs.…”

MicroRNA-223 Suppresses Osteoblast Differentiation by Inhibiting DHRS3

“…Retinaldehyde can then be reduced back to retinol by the RDH10-actvated DHRS3, or it can be further irreversibly oxidized to retinoic acid (RA) by the ALDH genes [22,26]. By functionally activating each other, DHRS3 and RDH10 work together to maintain the appropriate level of RA [23]. Many studies have demonstrated the significant role of RA in osteogenic differentiation.…”

“…DHRS3 plays a critical role in regulating the metabolism of RA. The expression of DHRS3 is upregulated when the amount of RA is excessive and downregulated when RA synthesis or signaling is blocked [23]. In mice, mutation of DHRS3 leads to excess RA in embryos [24].…”

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

“…In addition, before or early in their rostral migration, the amphibian organizer expresses multiple components of the retinoic acid biosynthetic network including RALDH2 (Chen, Pollet, Niehrs, & Pieler, ), RALDH3 (Lupo et al, ), RDH10 (Strate et al, ), DHRS3 (Richard K T Kam et al, ), and ADHFe1 (Shabtai, Shukrun, & Fainsod, ). Some of these components have also been described in other vertebrate embryos in analogous regions or their vicinity (Begemann et al, ; Blentic, Gale, & Maden, ; Grandel et al, ; Liang et al, ; Metzler & Sandell, ; Niederreither, Fraulob, Garnier, Chambon, & Dollé, ; Niederreither, McCaffery, Dräger, Chambon, & Dollé, ; Pittlik, Domingues, Meyer, & Begemann, ; Sandell et al, ; Swindell et al, ). These observations place multiple retinoic acid biosynthetic and signaling components in the embryonic organizer or its derivatives active in head induction.…”