Retinoic Acid Signaling in Neural Patterning

Introduction to Retinoic Acid

Retinoic acid, a key metabolite of vitamin A1, has shown its significant role in regulating the differentiation and proliferation of vitamin A1. Previous studies have demonstrated that all-trans-retinoic acid is essential for the growth of all chordates, ranging from fish to humans. The synthesis of retinoic acid consists of alcohol dehydrogenase and retinal dehydrogenase. The level of retinoic acid signaling is also mediated by retinoic acid-binding protein and retinol-binding proteins. Recently, all-trans-retinoic acid has been regarded as an intercellular signaling molecule to mediate the development of the anterior/posterior of the embryo. Moreover, retinoic acid can bind with retinoic acid receptors and retinoid X receptors to control the activation or release of various co-activators and co-inhibitors.

Fig.1 Pathways that are involved in the generation, action, and catabolism of retinoic acid. (Maden, 2007)

Retinoic Acid Signaling Pathway

Retinyl ester is hydrolyzed by microsomal carboxylesterase and other lipases to produce retinol, which is released into the bloodstream to form the retinol-binding complex protein 4(RBP4). Retinol/RBP4 complex can interact with STRA6 to bind its target cells. Furthermore, retinol binds to retinol-binding protein 1 and is oxidized to retinal by different kinds of retinol dehydrogenases, like RDH10 and Rdh1. Retinal will be catalyzed by a variety of retinal dehydrogenases, such as RALDH1, Aldh8a1, and Aldh1a1, to eventually converted to all-trans retinoic acid. All-trans retinoic acid is bind to its binding proteins to enter the nucleus. In the nucleus, retinoic acid can bind with the nuclear retinoic acid receptors and retinoid X receptors, including RARα, RARβ, RARγ, as well as RXRα to participate in a wide spectrum of tissue development processes.

Retinoic Acid Signaling in Neural Patterning

Currently, the role of retinoic acid signaling in neural patterning is becoming increasingly apparent. Recent studies have revealed that retinoic acid is associated with the differentiation, growth, development, regeneration of the nervous system. Numerous data have indicated that retinoic acid can be treated as a novel therapeutic molecule for mediating axon regeneration and treating various neurodegenerative diseases. During neural development, retinoic acid is used in conjunction with the supersonic hedgehog gene and bone morphogenetic protein to form the dorsal-ventral axis of the neural tube. Besides, retinoic acid can also regulate the differentiation of different neurons and glial cells by activating several signaling molecules, proteins, enzymes, and gene encoding transcription factors. Retinoic acid can act indirectly on neurons to stimulate the regenerative response. In the mature central nervous system, retinoic acid plays a significant role in maintaining plasticity and the production of neural stem cells. As a result. retinoic acid has been considered as a potential treatment target for neurological diseases, such as Parkinson's disease and Parkinson's disease.

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Reference

1. Maden, M.; et al. Retinoic acid in the development, regeneration, and maintenance of the nervous system. Nature Reviews Neuroscience. 2007, 8(10): 755-765.