Cell-Type-Specific Regulation of the Retinoic Acid Receptor Mediated by the Orphan Nuclear Receptor TLX

Abstract

Malformations in the eye can be caused by either an excess or deficiency of retinoids. An early target gene of the retinoid metabolite, retinoic acid (RA), is that encoding one of its own receptors, the retinoic acid receptor ␤ (RAR␤). To better understand the mechanisms underlying this autologous regulation, we characterized the chick RAR␤2 promoter. The region surrounding the transcription start site of the avian RAR␤2 promoter is over 90% conserved with the corresponding region in mammals and confers strong RA-dependent transactivation in primary cultured embryonic retina cells. This response is selective for RAR but not retinoid X receptor-specific agonists, demonstrating a principal role for RAR(s) in retina cells. Retina cells exhibit a far higher sensitivity to RA than do fibroblasts or osteoblasts, a property we found likely due to expression of the orphan nuclear receptor TLX. Ectopic expression of TLX in fibroblasts resulted in increased sensitivity to RA induction, an effect that is conserved between chick and mammals. We have identified a cis element, the silencing element relieved by TLX (SET), within the RAR␤2 promoter region which confers TLX-and RA-dependent transactivation. These results indicate an important role for TLX in autologous regulation of the RAR␤ gene in the eye.

Feedback Induction of a Photoreceptor-specific Isoform of Retinoid-related Orphan Nuclear Receptor β by the Rod Transcription Factor NRL

“…A unique feature of the Rorb gene is its sequential expression of both ROR␤1 and ROR␤2 isoforms in rod photoreceptors, which is coordinated by positive feedback by the downstream target, NRL rod differentiation factor. Another form of autoinduction of a nuclear receptor isoform during eye morphogenesis has been observed for the RAR␤2-specific promoter of the retinoic acid receptor ␤ gene in response to retinoic acid and the orphan nuclear receptor TLX (homolog of the Drosophila tailless protein) (47). Our results highlight the role of nuclear receptors, along with basic helix-loop-helix, homeodomain, and other classes of transcription factors (48 -50), in retinal cell differentiation.…”

Transcriptomic Analysis of Murine Embryos Lacking Endogenous Retinoic Acid Signaling

“…The Nr2e1 gene, encoding the orphan nuclear receptor Tlx, was also strongly downregulated in anterior tissues. A previous study pointed to Tlx as being involved in the regulation of the Rarb gene in the eye [43]. The SRY-box genes Sox1 (−1.66) and, to a lesser extent, Sox3 (−1.26), were also downregulated according to the ANT microarray experiment.…”

Nuclear Orphan Receptor TLX Induces Oct-3/4 for the Survival and Maintenance of Adult Hippocampal Progenitors upon Hypoxia

“…Strikingly, the mutation of the proximal retinoic acid response element resulted in a pronounced increase in the TLX-mediated up-regulation of the Oct-3/4 promoter activity. This is in contrast to the autologous regulation of retinoic acid response ␤ promoter where TLX synergizes with retinoic acid and alleviates the silencing of a Su-(var)3-9, Enhancer of Zeste (SET) element (40). Thus, similar to Sirtuin 1 (SIRT1) promoter, TLX could act as both transcriptional repressor and activator (41).…”

“…For example, the distal promoter controls Oct-3/4 in intracellular mass and ES cells, whereas the proximal enhancer and retinoic acid response elements control the epiblast/embryonic carcinoma state (35)(36)(37)(38). Because several nuclear orphan receptors bind to the Oct-3/4 promoter and TLX is a retinoid X acid receptor-related nuclear orphan receptor (6,40), we checked the effect of TLX on Oct-3/4 gene levels. Reporter assays using TLX and core Oct-3/4 promoter showed an increased promoter activity in the presence of TLX.…”