TLX is an orphan nuclear receptor that plays a critical role in both embryonic and adult 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 of natural and synthetic 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 (retinal), 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 mutational analysis provided insight into the molecular basis of retinoid binding to TLX. Our data support the validity of TLX as a target for development of therapeutics to treat cognitive disorders and/or glioblastomas.

TLX是一种孤儿核受体，在胚胎和成人神经发生以及胶质母细胞瘤的发病机理中都起着至关重要的作用。TLX主要起转录抑制子的作用，但尚未鉴定出天然配体或高亲和力合成配体。在这里，我们描述了天然和合成类视黄醇作为TLX的功能性配体的鉴定。我们确定了直接与TLX结合并激活或抑制其转录阻遏物活性的有效合成类维生素A。此外，我们确定了全反式和11-顺式视黄醛（视黄醛），在视力循环中起重要作用的类视黄醇，作为与TLX结合并调节其功能的优先天然类视黄醇。分子动力学模拟以及随后的突变分析提供了类视色素与TLX结合的分子基础的见解。我们的数据支持TLX作为开发用于治疗认知障碍和/或成胶质细胞瘤的疗法的目标的有效性。