#THE USED VULNERABLE II RAR RAR#
To assess spatio- and temporal RAR activation in vivo, RA-responsive reporter (RARE-β galactosidase) mice have been generated. Since signal transduction of vitamin A is controlled at many different levels, such as absorption, uptake, storage, transport, metabolism and gene expression, appropriate animal models are necessary to resolve the complexity of its physiological regulation. Furthermore, gene expression by RARs-RXRs is regulated by multiple transcriptional mediators (e.g. The endogenous RXR ligand 9CDHRA, with the ability to synergistically co-activate the RAR-RXR heterodimers, seems to derive from a vitamin A1-independent pathway. In the target tissues, ROH is taken up and either transported back to plasma for recycling to other tissues or oxidized to ATRA to activate RARs-RXRs. REs are hydrolysed to all- trans-retinol (ROH, vitamin A1 alcohol) and transported to the target tissues bound to a specific retinol-binding protein (RBP). Different from other nuclear receptor signalling systems, control of gene expression by vitamin A involves complexity at many different levels.īriefly, dietary vitamin A is absorbed in the intestine, and transported to the liver where it is stored in the form of retinyl esters (REs). Little is known about the main factors that are responsible for vitamin A signalling during adult life. It appears that ALDH1A2 and CYP26A1 and 2 are the main players for controlling vitamin A signalling for normal patterning and organogenesis in the embryo. CYP26A1–3) mainly generate localized gradients and distribution of ATRA. ĭuring embryonic development, enzymes responsible for ATRA synthesis (e.g. Ligand binding leads to a conformational change in the heterodimer, causing a release of co-repressors and recruitment of co-activators, which will promote induction of gene expression. The RARs and RXRs form heterodimers that bind to retinoic acid receptor response elements (RAREs) in regulatory regions of target genes. RARα, RARβ and RARγ) and three RXRs (i.e. These nuclear receptors, which all are transcription factors, consist of three related RARs (i.e. The majority of the effects of retinoids are mediated by the binding of all -trans-retinoic acid (ATRA) as the endogenous retinoic acid receptors (RARs) ligand and 9- cis-13,14-dihydroretinoic acid (9CDHRA), as the endogenous ligand of the RXRs. Retinoids are also indispensable throughout postnatal development for growth, reproduction, vision, maintenance of numerous tissues, and overall for survival. Vitamin A is required throughout embryogenesis to adult life, and proper levels of vitamin A derivatives, called retinoids, are crucial for normal morphogenesis during embryonic development. Conclusion: The RARE-luc transgenic mice, which enabled real-time in vivo assessment of RAR activation, will be useful in understanding the normal physiology of vitamin A, the role of retinoid signalling in pathologies as well as to evaluate pharmacological ligands for RARs. Luciferase activity was detectable in various organs, with high activity especially in brain and testis, indicating strong retinoid signalling in these tissues. These observations confirm that luciferase activity was controlled by RAR activation in the RARE-luc mouse. In addition, luciferase activity was strongly reduced in vitamin A-deficient mice (n=6–9 30 mice). Results: We found a strong induction of luciferase activity in a time and dose dependent manner by retinoic acid as well as RAR agonists, but not by the RXR agonist (using n=4–6 per group 94 mice). RARE dependent luciferase activity was detected by in vivo imaging or in tissue extracts following manipulations with RAR/retinoid X receptor (RXR) agonists, RAR antagonists or in vitamin A deficient mice. Methods: Transgenic mice carrying a RARE dependent luciferase reporter flanked with insulator sequence were generated by pronuclear injection. With the aim of developing an in vivo model to monitor retinoic acid receptor (RAR) transactivation real-time in intact animals, we generated transgenic mice carrying a luciferase (luc) reporter gene under the control of retinoic acid response elements (RAREs) consisting of three copies of a direct repeat with five spacing nucleotides (DR5). Background: Vitamin A is essential for a wide range of life processes throughout embryogenesis to adult life.
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