Institute of Cellular and Organismic Biology , Academia Sinica , Taipei 115 , Taiwan.
Department of Life Science , National Taiwan University , Taipei 10617 , Taiwan.
ACS Chem Neurosci. 2019 Sep 18;10(9):4031-4042. doi: 10.1021/acschemneuro.9b00273. Epub 2019 Aug 23.
Aryl hydrocarbon receptor (AHR) signaling has been suggested to play roles in various physiological functions independent of its xenobiotic activity, including cell cycle regulation, immune response, and embryonic development. Several endogenous ligands were also identified by high-throughput screening techniques. However, the mechanism by which these molecules mediate AHR signaling in certain functions is still elusive. In this study, we investigated the possible pathway through which AHR and its endogenous ligands regulate neural development. We first identified two neuroactive steroids, 3α,5α-tetrahydrocorticosterone and 3α,5β-tetrahydrocorticosterone (5α- and 5β-THB), as novel AHR endogenous ligands through the use of an ultrasensitive dioxin-like compound bioassay and liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS). We then treated zebrafish embryos with 5α- and 5β-THB, which enhance the expression of neurogenesis marker HuC. Furthermore, 5α- and 5β-THB both enhanced the expression of myelinating glial cell markers, sex determining region Y-box 10 (Sox10), and myelin-associated proteins myelin basic protein (Mbp) and improved the mobility of zebrafish larvae via the Ahr2 pathway. These results indicated that AHR mediates zebrafish neurogenesis and gliogenesis, especially the differentiation of oligodendrocyte or Schwann cells. Additionally, we showed that these molecules may induce neuroblastoma (NB) cell differentiation suggesting therapeutic potential of 5α- and 5β-THB in NB treatment. In summary, our results reveal that 5α- and 5β-THB are endogenous ligands of AHR and have therapeutic potential for NB treatment. By the interaction with THB, AHR signaling regulates various aspects of neural development.
芳香烃受体 (AHR) 信号转导被认为在多种生理功能中发挥作用，而这些功能与其外源性活性无关，包括细胞周期调节、免疫反应和胚胎发育。通过高通量筛选技术，还鉴定出了几种内源性配体。然而，这些分子在某些功能中介导 AHR 信号转导的机制仍不清楚。在这项研究中，我们研究了 AHR 及其内源性配体调节神经发育的可能途径。我们首先通过使用超灵敏二恶英样化合物生物测定法和液相色谱-电喷雾电离串联质谱法 (LC-ESI-MS)，鉴定出两种神经活性甾体，3α,5α-四氢皮质酮和 3α,5β-四氢皮质酮（5α-和 5β-THB），作为新型 AHR 内源性配体。然后，我们用 5α-和 5β-THB 处理斑马鱼胚胎，这会增强神经发生标志物 HuC 的表达。此外，5α-和 5β-THB 均增强了髓鞘形成胶质细胞标志物性别决定区 Y 盒 10 (Sox10) 的表达，并通过 Ahr2 途径改善了斑马鱼幼虫的迁移能力。这些结果表明 AHR 介导了斑马鱼的神经发生和神经胶质发生，特别是少突胶质细胞或施万细胞的分化。此外，我们表明这些分子可能诱导神经母细胞瘤 (NB) 细胞分化，提示 5α-和 5β-THB 在 NB 治疗中的治疗潜力。总之，我们的结果表明 5α-和 5β-THB 是 AHR 的内源性配体，具有 NB 治疗的治疗潜力。通过与 THB 的相互作用，AHR 信号转导调节了神经发育的各个方面。
