CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, CAS Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Basic Clinical Research Center, Renji Hospital, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Key Laboratory of Reproductive Medicine, Shanghai JiaoTong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China.
Stem Cell Reports. 2019 Dec 10;13(6):1038-1052. doi: 10.1016/j.stemcr.2019.10.013. Epub 2019 Nov 21.
The generation of brain region-specific progenitors from human embryonic stem cells (hESCs) is critical for their application. However, transcriptional regulation of neural regionalization in humans is poorly understood. Here, we applied a rostrocaudal patterning system from hESCs to dissect global transcriptional networks controlling early neural regionalization. We found that SOX21 is required for rostral forebrain fate specification. SOX21 knockout led to activation of Wnt signaling, resulting in caudalization of regional identity of rostral forebrain neural progenitor cells. Moreover, we identified WNT8B as a SOX21 direct target. Deletion of WNT8B or inhibition of Wnt signaling in SOX21 knockout neural progenitor cells restored rostral forebrain identity. Furthermore, SOX21 interacted with β-catenin, interfering with the binding of TCF4/β-catenin complex to the WNT8B enhancer. Collectively, these results unveil the unknown role of SOX21 and shed light on how a transcriptional factor modulates early neural regionalization through crosstalk with a key component of Wnt signaling.
从人类胚胎干细胞 (hESC) 中生成脑区特异性祖细胞对于其应用至关重要。然而，人类神经区域化的转录调控知之甚少。在这里，我们应用 hESC 的头尾模式系统来剖析控制早期神经区域化的全局转录网络。我们发现 SOX21 对于额前脑命运特化是必需的。SOX21 敲除导致 Wnt 信号的激活，导致额前脑神经祖细胞的区域特征向尾部化。此外，我们鉴定出 WNT8B 是 SOX21 的直接靶标。在 SOX21 敲除神经祖细胞中缺失 WNT8B 或抑制 Wnt 信号可以恢复额前脑特征。此外，SOX21 与 β-catenin 相互作用，干扰 TCF4/β-catenin 复合物与 WNT8B 增强子的结合。总之，这些结果揭示了 SOX21 的未知作用，并阐明了转录因子如何通过与 Wnt 信号的关键成分相互作用来调节早期神经区域化。
