Cell-type-specific regulation of the retinoic acid receptor mediated by the orphan nuclear receptor TLX

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 beta (RAR beta). To better understand the mechanisms underlying this autol ogous regulation, we characterized the chick RAR beta2 promoter. The region surrounding the transcription start site of the avian RAR beta2 promoter i s over 90% conserved with the corresponding region in mammals and confers s trong RA-dependent transactivation in primary cultured embryonic retina cel ls. This response is selective for RAR but not retinoid X receptor-specific agonists, demonstrating a principal role for RAR(s) in retina cells. Retin a cells exhibit a far higher sensitivity to RA than do fibroblasts or osteo blasts, a property we found likely due to expression of the orphan nuclear receptor TLX. Ectopic expression of TLX in fibroblasts resulted in increase d sensitivity to RA induction, an effect that is conserved between chick an d mammals. We have identified a cis element, the silencing element relieved by TLX (SET), within the RAR beta2 promoter region which confers TLX- and RA-dependent transactivation. These results indicate an important role for TLX in autologous regulation of the RAR beta gene in the eye.