The Orphan Nuclear Receptor TLX is a Receptor for Synthetic and Natural Retinoids

TLX is an orphan nuclear receptor that plays a role in  neurogenesis as well in the pathogenesis of glioblastomas.TLX functions predominately as a transcriptional repressor, but no natural ligands or high affinity synthetic ligands have been identified.  Here, we describe the identification retinoids as functional ligands for TLX.  We identified potent synthetic retinoids that directly bind to TLX and either activate or inhibit its transcriptional repressor activity.  Furthermore, we identified all-trans and 11-cis retinaldehyde, retinoids that play an essential role in the visual cycle, as the preferential natural retinoids that bind to and modulate the function of TLX. Molecular dynamics simulations followed by confirmation by mutational analysis revealed the basis of retinoid binding to TLX. Our data suggests that retinoids may play a physiological role in modulation of TLX activity and support the validity of TLX as a target for development of therapeutics to treat cognitive disorders and/or glioblastomas.