Retinoic acid (used simplified here for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that mediates the functions of vitamin A1 required for growth and development. All-trans-retinoic acid is needed in chordate animals, which has all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps confirm position on the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes that ultimately management anterior/posterior patterning biological process stages. All-trans-retinoic acid (ATRA) is the major occurring retinoic acid, while isomers like 13-cis- and 9-cis-retinoic acid are also present in much lower levels. The key role of all-trans-retinoic acid in embryonic development regulates the high teratogenicity of retinoid prescribed drugs, such as isotretinoin/13-cis-retinoic acid used for treatment of cancer and disease of the skin. Oral megadoses of pre-formed vitamin A (retinyl palmitate), and all-trans-retinoic acid itself, also have teratogenic potential by this same mechanism.
Figure 1. Chemical structure of all-trans-retinoic acid.
Mechanism of biological action
All-trans-retinoic acid acts by binding to the retinoic acid receptor (RAR), that is guaranteed to polymer as a heterodimer with the retinoid X receptor (RXR) in regions known as retinoic acid response parts (RAREs). Binding of the all-trans-retinoic acid ligand to RAR alters the conformation of the RAR, which affects the binding of other proteins that either induce or repress transcription of a nearby gene (including Hox genes and several other target genes). Retinoic acid receptors (RARs) mediate transcription of various sets of genes dominant differentiation of a wide range of cell types, thus the target genes regulated depend on the target cells. In some cells, one in every of the target genes is that the gene for the retinoic acid receptor itself (RAR-beta in mammals) that amplifies the response. Management of retinoic acid levels is maintained by a collection of proteins that control synthesis and degradation of retinoic acid. The molecular basis for the interaction between all-trans-retinoic acid and the Hox genes has been studied by using deletion analysis in transgenic mice carrying constructs of GFP reporter genes. Such studies have identified functional RAREs within flanking sequences of some of the most 3' Hox genes (including Hoxa1, Hoxb1, Hoxb4, Hoxd4), suggesting a direct interaction between the genes and retinoic acid. These sorts of studies powerfully support the normal roles of retinoids in patterning vertebrate embryogenesis through the Hox genes.
In some cells, one in every of the target cistrons is that the gene for the retinoic acid receptor itself (RAR-beta in mammals), that amplifies the response. management of retinoic acid levels is maintained by a collection of proteins that management synthesis and degradation of retinoic acid.
Retinoid receptors are nuclear receptors (a category of proteins) that bind to retinoids. When they bound to a retinoid, they could act as transcription factors, fixing the expression of genes with corresponding response parts. Significant age-related declines in the levels of retinoid receptors in the forebrains of rats have been reversed by supplementation with the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which can restore neurogenesis. Subtypes include: Retinoic acid receptors (RARs), Retinoid X receptors (RXRs) and RAR-related orphan receptors (RORs). The retinoic acid receptor (RAR) could be a kind of nuclear receptor which may conjointly act as a transcription factor that is activated by all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. Each receptor isoform has ten splice variants: four for alpha, four for beta, and two for gamma. Like different type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements referred to as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation.
1. Venkatesh K.; et al. In vitro differentiation of cultured human CD34+ cells into astrocytes. Neurol India. 2013, 61:383-388.
2. Molotkov, A.; et al. Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation. Biochemical Journal. 2004, 383: 295–302.
3. Dyall SC.; et al. Omega-3 fatty acids reverse age-related decreases in nuclear receptors and increase neurogenesis in old rats. Journal of Neuroscience Research. 2010, 88(10): 2091–2102.