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Retinoic acid (simplified nomenclature for all- trans-retinoic acid) is a metabolite of vitamin A1 (all- trans-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All- trans-retinoic acid is required for chordate animal development, which includes all higher animals from fish to humans. During early embryonic development, all- trans-retinoic acid generated in a specific region of the embryo helps determine position along 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 , which ultimately control anterior/posterior patterning in early developmental stages. In adult tissues, the activity of endogenous retinoic acid appears limited to immune function and male fertility.
All- trans-retinoic acid 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 mediates the high teratogenicity of retinoid pharmaceuticals, such as isotretinoin (13- cis-retinoic acid) used for treatment of acne or retinol used for skin disorders. High oral doses of preformed vitamin A (retinyl palmitate), and all- trans-retinoic acid itself, also have teratogenic potential by this same mechanism.
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 gene. 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 types of studies strongly support the normal roles of retinoids in patterning vertebrate embryogenesis through the Hox genes.
In adults, retinoic acid has a key role in preventing autoimmunity in mucosal tissues. Retinoic acid produced by dendritic cells promotes regulatory T cell formation to promote tolerance within the colon. This pathway is used by cancer cells to suppress the immune system. In the testes, retinoic acid is necessary for the process of spermatogenesis. Experiments in healthy male subjects suggests that retinoic acid is only necessary for fertility in adult humans.
Retinoic acid plays a complex role in cancer. In some types of cancer cells that express retinoic acid receptors retinoic acid causes differentiation, while in other types of cancer cells that lack critical components of the retinoic acid signaling pathways retinoic acid may promote cancer progression by suppressing the immune response, and by promoting a dormant state in cancer cells whereby decreased proliferation and metabolism protects them from chemotherapy.
A double-sided retinoic acid gradient that is high in the trunk and low at the junction with the head and tail represses fibroblast growth factor 8 in the developing trunk to allow normal somitogenesis, forelimb limb bud initiation, and formation of the atria in the heart. During exposure to excess retinoic acid, the hindbrain becomes enlarged, hindering the growth of other parts of the brain; other developmental abnormalities that can occur during excess retinoic acid are missing or fused Somite, and problems with the aorta and large vessels within the heart. With an accumulation of these malformations, an individual can be diagnosed with DiGeorge syndrome. However, since retinoic acid acts in various developmental processes, abnormalities associated with loss of retinoic acid are not only limited to sites associated with DiGeorge syndrome. Genetic loss-of-function studies in mouse and zebrafish embryos that eliminate retinoic acid synthesis or retinoic acid receptors (RARs) have revealed abnormal development of the somites, forelimb buds, heart, hindbrain, spinal cord, eye, forebrain basal ganglia, kidney, foregut endoderm, etc.
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