7-RARalpha updated review

7-RARalpha updated review - REVIEWS Retinoic acid in the...

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It is becoming increasingly apparent that the role of developmental signalling molecules is not over when embryogenesis has been completed. In the adult, such molecules might function in the maintenance of stem cell proliferation, the regeneration of tissues and organs, and even in the maintenance of their differen- tiated state. This makes economical and evolutionary sense because, as has long been argued, in order to regenerate an organ, all that might be required is the re-awakening of the signalling systems that were origi- nally used to develop it. If so, developmental signal- ling molecules might be crucial for understanding and treating disease states in adults. This Review explores this concept, focusing on retinoic acid (RA) and the nervous system. RA is an established signalling molecule that is involved in neuronal patterning, neural differentiation and axon outgrowth. In its absence, some aspects of these events do not occur. Recent data highlight roles for RA in generating specific neuronal cell types for therapeutic transplantation and in regenerating axons after damage. In addition, RA is involved in the main- tenance of the differentiated state of adult neurons and neural stem cells, and altered RA signalling levels lead to the appearance of symptoms of some neurode- generative diseases. Studies suggest that this molecule could be therapeutically useful for both the induction of nervous system regeneration and the treatment of neurodegeneration. The RA signalling pathway RA is a metabolic product of vitamin A (retinol). Animals cannot synthesize vitamin A so they must extract it from their diet in the form of carotenoids (from plants) and reti- nyl esters (from animal products). These dietary compo- nents are stored as retinyl esters (also known as retinoids) in the liver and in several extrahepatic sites, including the lungs, bone marrow and the kidneys 1 . Transport of retinoids from these storage sites to the cells that require them is performed by retinol, which is released into the bloodstream and circulates bound to retinol-binding protein 4, plasma ( RBP4 ). Retinol is taken up by target cells through an interaction with a membrane receptor for RBP4, STRA6 (REF. 2); it then enters the cytoplasm, where it binds to retinol-binding protein 1, cellular (RBP1) and is metabolized in a two-step process to all- trans RA 3 (FIG. 1) . In many cell types, two cytoplasmic proteins — cellular retinoic-acid-binding proteins 1 and 2 ( CRABP1 and CRABP2 ) — bind to the newly synthesized RA. When signalling in a paracrine fashion, RA must be released from the cytoplasm (by unknown mechanisms) and taken up by receiving cells; however, RA can also act in an autocrine manner (FIG. 1) . RA enters the nucleus, assisted by CRABP2 (REF. 4) , and binds to a transcrip- tion complex which includes a pair of ligand-activated transcription factors comprising the RA receptor (RAR)–retinoic X receptor (RXR) heterodimer. There are three RAR genes (
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This note was uploaded on 05/26/2011 for the course BIO 445 taught by Professor Staff during the Spring '11 term at UNC.

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7-RARalpha updated review - REVIEWS Retinoic acid in the...

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