Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Mol Cell Endocrinol. 2018 Aug 15;471:51-62. doi: 10.1016/j.mce.2017.07.033. Epub 2017 Aug 2.
Retinoid X Receptors (RXRs) are unique and enigmatic members of the nuclear receptor (NR) family with extensive and complex biological functions in cellular differentiation. On the one hand, RXRs through permissive heterodimerization with other NRs are able to integrate multiple lipid signaling pathways and are believed to play a central role to coordinate the development of the central nervous system. On the other hand, RXRs may have heterodimer-independent functions as well. Therefore, a more RXR-centric analysis is warranted to identify its genomic binding sites and regulated gene networks, which are orchestrating the earliest events in neuronal differentiation. Recently developed genome-wide approaches allow systematic analyses of the RXR-driven neural differentiation. Here we applied next generation sequencing-based methodology to track the dynamic redistribution of the RXR cistrome along the path of embryonic stem cell to glutamatergic neuron differentiation. We identified Retinoic Acid Receptor (RAR) and Liver X Receptor (LXR) as dominant heterodimeric partners of RXR in these cellular stages. Our data presented here characterize the RAR:RXR and LXR:RXR-mediated transcriptional program in embryonic stem cells, neural progenitors and terminally differentiated neurons. Considering the growing evidence for dysregulated RXR-mediated signaling in neurodegenerative disorders, such as Alzheimer's Disease or Amyotrophic Lateral Sclerosis, the data presented here will be also a valuable resource for the field of neuro(patho)biology.
视黄酸受体 X（RXR）是核受体（NR）家族中独特而神秘的成员，在细胞分化中具有广泛而复杂的生物学功能。一方面，RXR 通过与其他 NR 的许可性异二聚化能够整合多种脂质信号通路，并被认为在协调中枢神经系统发育方面发挥核心作用。另一方面，RXR 也可能具有异二聚体非依赖性的功能。因此，更以 RXR 为中心的分析是必要的，以识别其基因组结合位点和调节的基因网络，这些网络协调神经元分化的最早事件。最近开发的全基因组方法允许对 RXR 驱动的神经分化进行系统分析。在这里，我们应用基于下一代测序的方法来跟踪 RXR 顺式作用元件沿着胚胎干细胞向谷氨酸能神经元分化路径的动态重分布。我们确定了视黄酸受体（RAR）和肝 X 受体（LXR）作为这些细胞阶段中 RXR 的主要异二聚体伙伴。我们在此呈现的数据描绘了 RAR:RXR 和 LXR:RXR 介导的胚胎干细胞、神经祖细胞和终末分化神经元中转录程序。考虑到在神经退行性疾病（如阿尔茨海默病或肌萎缩性侧索硬化症）中 RXR 介导的信号转导失调的证据不断增加，这里呈现的数据也将成为神经（病理）生物学领域的宝贵资源。
