Abstract
The retinoid X receptors (RXRs) are ligand-activated transcription factors which heterodimerize with a number of nuclear hormone receptors, thereby controlling a variety of (patho)-physiological processes. Although synthetic RXR ligands are developed for the treatment of various diseases, endogenous ligand(s) for these receptors have not been conclusively identified. We show here that mice lacking cellular retinol binding protein (Rbp1-/-) display memory deficits reflecting compromised RXR signaling. Using HPLC-MS and chemical synthesis we identified in Rbp1-/- mice reduced levels of 9-cis-13,14-dihydroretinoic acid (9CDHRA), which acts as an RXR ligand since it binds and transactivates RXR in various assays. 9CDHRA rescues the Rbp1-/- phenotype similarly to a synthetic RXR ligand and displays similar transcriptional activity in cultured human dendritic cells. High endogenous levels of 9CDHRA in mice indicate physiological relevance of these data and that 9CDHRA acts as an endogenous RXR ligand.
Highlights
Micronutrients such as vitamin A and polyunsaturated fatty acids are essential ingredients of mammalian diet and can act as bioactive molecules
In order to search for endogenous retinoids which may act as Retinoid X receptors (RXRs) ligand(s), we first employed behavioral and pharmacological analyses sensitive to RXR signaling as a tool to identify animal models with reduced RXR signaling
Using delayed non-match to place (DNMTP) task, we found that mice carrying a null mutation of cellular retinol binding protein I (RBP1), known for its role in retinoid metabolism [29], display memory deficits which phenocopy the effect of the loss of function of Rxrγ, a functionally predominant RXR in control of working memory (Fig 1A and ref. [3])
Summary
Micronutrients such as vitamin A and polyunsaturated fatty acids are essential ingredients of mammalian diet and can act as bioactive molecules. Among complex functions, working memory was shown sensitive to RXR ligand activities in mice [3], whereas at the cellular and molecular level, differentiation of monocyte-derived dendritic cells is one of the well characterized experimental models used to study the activities of RXR ligands [4,5]. Such ligands are known to act as powerful inducers of apoptosis in cancer cells [6,7] or as modulators of lipid and glucose metabolism, which has stimulated their clinical development for the treatment of cancer and metabolic diseases [8]. Recent studies on antidepressant or neuro-regenerative activities of RXR specific agonists suggest their utility for the treatment of some neuropsychiatric or neurodegenerative disorders [3,9,10]
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