HGNC Approved Gene Symbol: RXRB
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:33,193,588-33,200,853 (from NCBI)
The retinoic acid receptors, alpha (RARA; 180240), beta (RARB; 180220), and gamma (RARG; 180190), require coregulators to bind effectively to response elements and target genes. By a strategy of sequential screening of expression libraries with a retinoic acid response element and RAR, Yu et al. (1991) identified a cDNA encoding a coregulator highly related to RXR-alpha (180245), termed RXR-beta.
Fleischhauer et al. (1993) isolated a full-length cDNA clone encoding human RXRB by nucleic acid screening of a human cDNA library with a fragment of the mouse Rxrb gene as a probe. Comparison of human and murine RXRB showed 97.6% identity on the amino acid level and 91.6% on the nucleotide level.
Yu et al. (1991) demonstrated that RXR-beta formed heterodimers with RAR, preferentially increasing its DNA binding and transcriptional activity on promoters containing retinoic acid, but not thyroid hormone or vitamin D, response elements. Remarkably, RXR-beta also heterodimerized with thyroid hormone and vitamin D receptors, increasing both DNA binding and transcriptional function on their respective response elements. RXR-alpha also formed heterodimers with these receptors. These observations suggested that retinoid X receptors meet the criteria for biochemically characterized cellular coregulators and serve to target selectively the high affinity binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate DNA response elements.
Using RFLVs in interspecific backcross mice, Hoopes et al. (1992) mapped the Rxrb gene to the H-2 region of chromosome 17. By homology, it is likely that the RXRB gene in the human is located on 6p. Fleischhauer et al. (1993) demonstrated that this is indeed the case. They showed that the RXRB gene is located in the 6pter-q13 region by Southern hybridization of genomic DNA from human/rodent cell hybrids with the mouse gene as a probe. With the relatively crude mapping methods used, Fleischhauer et al. (1993) could not map RXRB more precisely than to the short arm of chromosome 6 and/or the proximal part of the long arm; however, the findings are at least consistent with location in the HLA region, as suggested by homology.
Fitzgibbon et al. (1993) mapped the RXRB gene to 6p21.3-p21.1 by PCR amplification of 5-prime untranslated sequence in panels of rodent-human somatic cell hybrids and to 6p21.3 by fluorescence in situ hybridization. By pairwise hybridization of an RXRB cosmid and reference markers in fluorescence in situ hybridization, Almasan et al. (1994) likewise mapped the RXRB gene to 6p21.3. Using cosmid clones that cover the major histocompatibility complex (MHC) region, Nagata et al. (1995) determined the precise physical map positions of the RXRB gene relative to the MHC genes in mouse and human. Conservation of gene organization was observed between the 2 species at the HLA-DP (142880) region.
RARB, RARG, RXRB, and RXRG (180247) are expressed in the striatum. To study the effect of these genes on locomotion, Krezel et al. (1998) developed single and double knockout mice and analyzed their locomotor skills by open field and rotarod testing. RARB-RXRB, RARB-RXRG, and RXRB-RXRG double-null mutant mice, but not the corresponding single-null mutants, exhibited reductions in forward locomotion when compared with wildtype littermates. Forty percent of the RARB-RXRB-null mutants showed backward locomotion. Rotarod test performance was impaired for RARB, RARB-RXRB, RARB-RXRG, and RXRB-RXRG mice. In contrast, RARA, RARG, RARA-RXRG, and RARG-RXRG-null mice showed no defects in locomotion, even though both RARA and RARG are also expressed in the striatum. The morphology, development, and function of skeletal muscle, peripheral nerves, and spinal cord were normal in all single and double-null mutants, as were balance reflexes. These results suggested to Krezel et al. (1998) that RARB, RXRB, and RXRG are involved specifically in the control of locomotor behaviors, and that heterodimers of RARB with either RXRB or RXRG are the functional receptor units, such that RXRB and RXRG are functionally redundant. Krezel et al. (1998) studied the expression of D1 and D2 dopamine receptors (D1R; 126449 and D2R; 126450), the most abundant dopamine receptors in the striatum, in these mutant mice. RARB-RXRB, RARB-RXRG, and RXRB-RXRG double-null mutants, but not RARB or RXRG single mutants, exhibited 40% and 30% reduction in whole-striatal D1R and D2R transcripts, respectively, when compared with wildtype controls. The reduction was mostly in the medioventral regions of the striatum, including the shell and core of the nucleus accumbens, and the mediodorsal part of the caudate putamen. The reduction was not due to loss of D2R-expressing neurons; no increase in apoptosis was noted. The histology of the striatum was normal. The characterization of a retinoic acid response element in the D2R promoter by Samad et al. (1997) led Krezel et al. (1998) to suggest that the reduction in D2R and D2R expression occurs on a transcriptional level. The RARB-RXRB, RARB-RXRG, and RXRB-RXRG double-null mutants did not exhibit the normal increase in locomotion induced by cocaine, mimicking the phenotype of D1R-null mice. Taken together, these results indicated to Krezel et al. (1998) that retinoids are involved in controlling the function of the dopaminergic mesolimbic pathway and suggested that defects in retinoic acid signaling may contribute to disorders such as Parkinson disease and schizophrenia.
In an elegant series of experiments designed to understand the effect of RXR activation on cholesterol balance, Repa et al. (2000) treated animals with the rexinoid LG268. Animals treated with rexinoid exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs, see 602423 and 600380) and the bile acid receptor, FXR (603826), are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse-cholesterol transporter, ABC1 (600046), and the rate-limiting enzyme of bile acid synthesis, CYP7A1 (118455), respectively. These RXR heterodimers serve as key regulators in cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine. Activation of RXR/LXR heterodimers inhibits cholesterol absorption by upregulation of ABC1 expression in the small intestine. Activation of RXR/FXR heterodimers represses CYP7A1 expression and bile acid production, leading to a failure to solubilize and absorb cholesterol. Studies have shown that RXR/FXR-mediated repression of CYP7A1 is dominant over RXR/LXR-mediated induction of CYP7A1, which explains why the rexinoid represses rather than activates CYP7A1 (Lu et al., 2000). Activation of the LXR signaling pathway results in the upregulation of ABC1 in peripheral cells, including macrophages, to efflux free cholesterol for transport back to the liver through high density lipoprotein, where it is converted to bile acids by the LXR-mediated increase in CYP7A1 expression. Secretion of biliary cholesterol in the presence of increased bile acid pools normally results in enhanced reabsorption of cholesterol; however, with the increased expression of ABC1 and efflux of cholesterol back into the lumen, there is a reduction in cholesterol absorption and net excretion of cholesterol and bile acid. Rexinoids therefore offer a novel class of agents for treating elevated cholesterol.
Almasan, A., Mangelsdorf, D. J., Ong, E. S., Wahl, G. M., Evans, R. M. Chromosomal localization of the human retinoid X receptors. Genomics 20: 397-403, 1994. [PubMed: 8034312] [Full Text: https://doi.org/10.1006/geno.1994.1193]
Fitzgibbon, J., Gillett, G. T., Woodward, K. J., Boyle, J. M., Wolfe, J., Povey, S. Mapping of RXRB to human chromosome 6p21.3. Ann. Hum. Genet. 57: 203-209, 1993. [PubMed: 8257090] [Full Text: https://doi.org/10.1111/j.1469-1809.1993.tb01596.x]
Fleischhauer, K., McBride, O. W., DiSanto, J. P., Ozato, K., Yang, S. Y. Cloning and chromosome mapping of human retinoid X receptor beta: selective amino acid sequence conservation of a nuclear hormone receptor in mammals. Hum. Genet. 90: 505-510, 1993. [PubMed: 8381386] [Full Text: https://doi.org/10.1007/BF00217449]
Hoopes, C. W., Taketo, M., Ozato, K., Liu, Q., Howard, T. A., Linney, E., Seldin, M. F. Mapping the mouse Rxr loci encoding nuclear retinoid X receptors Rxr-alpha, Rxr-beta, and Rxr-gamma. Genomics 14: 611-617, 1992. [PubMed: 1358808] [Full Text: https://doi.org/10.1016/s0888-7543(05)80159-4]
Krezel, W., Ghyselinck, N., Samad, T. A., Dupe, V., Kastner, P., Borrelli, E., Chambon, P. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279: 863-867, 1998. [PubMed: 9452386] [Full Text: https://doi.org/10.1126/science.279.5352.863]
Lu, T. T., Makishima, M., Repa, J. J., Schoonjans, K., Kerr, T. A., Auwerx, J., Mangelsdorf, D. J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Molec. Cell 6: 507-515, 2000. [PubMed: 11030331] [Full Text: https://doi.org/10.1016/s1097-2765(00)00050-2]
Nagata, T., Weiss, E. H., Abe, K., Kitagawa, K., Ando, A., Yara-Kikuti, Y., Seldin, M. F., Ozato, K., Inoko, H., Taketo, M. Physical mapping of the retinoid X receptor B gene in mouse and human. Immunogenetics 41: 83-90, 1995. [PubMed: 7806300] [Full Text: https://doi.org/10.1007/BF00182317]
Repa, J. J., Turley, S. D., Lobaccaro, J.-M. A., Medina, J., Li, L., Lustig, K., Shan, B., Heyman, R. A., Dletschy, J. M., Mangelsdorf, D. J. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289: 1524-1529, 2000. [PubMed: 10968783] [Full Text: https://doi.org/10.1126/science.289.5484.1524]
Samad, A., Krezel, W., Chambon, P., Borrelli, E. Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family. Proc. Nat. Acad. Sci. 94: 14349-14354, 1997. [PubMed: 9405615] [Full Text: https://doi.org/10.1073/pnas.94.26.14349]
Yu, V. C., Delsert, C., Andersen, B., Holloway, J. M., Devary, O. V., Naar, A. M., Kim, S. Y., Boutin, J.-M., Glass, C. K., Rosenfeld, M. G. RXR-beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 67: 1251-1266, 1991. [PubMed: 1662118] [Full Text: https://doi.org/10.1016/0092-8674(91)90301-e]