Retinoic acid synthesis and functions in early embryonic development

Abstract

Retinoic acid (RA) is a morphogen derived from retinol (vitamin A) that plays important roles in cell growth, differentiation, and organogenesis. The production of RA from retinol requires two consecutive enzymatic reactions catalyzed by different sets of dehydrogenases. The retinol is first oxidized into retinal, which is then oxidized into RA. The RA interacts with retinoic acid receptor (RAR) and retinoic acid X receptor (RXR) which then regulate the target gene expression. In this review, we have discussed the metabolism of RA and the important components of RA signaling pathway, and highlighted current understanding of the functions of RA during early embryonic development.

Expression profiles of retinoic acid synthetases ALDH1As and metabolic enzymes CYP26s in adult and embryonic zebrafish (Danio rerio)

“…The level of RA present in a given tissue is tightly controlled by the metabolic machinery of synthesis and degradation, setting up a pre-receptor system that directs the timing and tissue specificity of RA signaling (Kam et al, 2012). RA is synthesized by the sequential oxidation of retinol.…”

Heat Shock 70-kDa Protein 5 (Hspa5) Is Essential for Pronephros Formation by Mediating Retinoic Acid Signaling

“…In early Xenopus gastrulae, treatment with all-trans-retinoic acid (atRA) and activin induces pluripotent ectodermal cells to differentiate into pronephros tissue (11)(12)(13)(14). Inhibition of RA signaling impairs pronephros formation (15,16). During early embryonic development, RA signaling is initiated mainly by atRA, a metabolite of vitamin A. atRA binds to a family of nuclear receptors, RARs (␣/␤/␥), which in turn form heterodimers with retinoid X receptors (RXRs) (␣/␤/␥) to activate expression of RA response element (RARE)-containing target genes (16,17).…”

“…Inhibition of RA signaling impairs pronephros formation (15,16). During early embryonic development, RA signaling is initiated mainly by atRA, a metabolite of vitamin A. atRA binds to a family of nuclear receptors, RARs (␣/␤/␥), which in turn form heterodimers with retinoid X receptors (RXRs) (␣/␤/␥) to activate expression of RA response element (RARE)-containing target genes (16,17). lhx1 is one of the earliest genes that is expressed in the nephric mesenchyme and has been implicated in kidney development (18 -22).…”

Vitamins for the First 1000 Days: Preparing for Life

“…It is a major cause of xerophthalmia, night blindness, and anemia [5]. Moreover, it is essential for immune functions and mucosal integrity, and inadequate supply is associated with a higher susceptibility for intestinal and respiratory infections [6,7]. Through its role in gene regulation, vitamin A is involved in fetal development, organogenesis, limb formation, and body symmetry.…”

“…the nuclear retinoic acid receptors (RAR) and the retinoid X receptors (RXR) build heterodimers with each other and, in the case of RXR, also with other nuclear receptors like PPARs or vitamin D receptor, and act as ligand-activated transcription factors via retinoid acid response elements (RARE). During fetal development, they regulate cell differentiation through morphogenetic processes based on local concentration gradients [7]. Defi ciency during pregnancy can thus result in teratogenic effects on various organs and tissues such as the heart, eyes, the circulatory, pulmonary, urogenitary and central nervous systems, especially the hindbrain.…”