Impaired generation of mature neurons due to extended expression of Tlx by repressing Sox2 transcriptional activity,STEM CELLS

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Impaired generation of mature neurons due to extended expression of Tlx by repressing Sox2 transcriptional activity
STEM CELLS ( IF 4.0 ) Pub Date : 2021-07-16 , DOI: 10.1002/stem.3435
Yu Wang _{1,

2} , Bin Li ₁ , Lianwei Dong ₃ , Weibing Duan _{4,

5} , Anna Neuerburg ₆ , Han Zhang ₂ , Xijuan Jiang ₁ , Rui Shao ₄ , Yan Zhu ₄ , Dagmar Bock ₆ , Erwei Liu ₂ , Hong Wang ₁ , Yunsha Zhang ₁ , Yifan Dai _{7,

8} , Haiyuan Yang _{7,

8} , Ying Wang _{7,

8}

Affiliation

School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
Laboratory of Pharmacology of TCM Formulae Co-Constructed by the Province-Ministry, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
Department of Cardiovascular Medicine, The People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, People's Republic of China.
Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, People's Republic of China.
Jian Central People's Hospital, Jian, Jiangxi, People's Republic of China.
Division of Molecular Biology of the Cell I, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, People's Republic of China.
Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, People's Republic of China.

As a master regulator of the dynamic process of adult neurogenesis, timely expression and regulation of the orphan nuclear receptor Tailless (Tlx) is essential. However, there is no study yet to directly investigate the essential role of precise spatiotemporal expressed Tlx. Here, we generated a conditional gain of Tlx expression transgenic mouse model, which allowed the extended Tlx expression in neural stem cells (NSCs) and their progeny by mating with a TlxCreER^T2 mouse line. We demonstrate that extended expression of Tlx induced the impaired generation of mature neurons in adult subventricular zone and subgranular zone. Furthermore, we elucidated for the first time that this mutation decreased the endogenous expression of Sox2 by directly binding to its promoter. Restoration experiments further confirmed that Sox2 partially rescued these neuron maturation defects. Together, these findings not only highlight the importance of shutting-off Tlx on time in controlling NSC behavior, but also provide insights for further understanding adult neurogenesis and developing treatment strategies for neurological disorders.

中文翻译：

通过抑制 Sox2 转录活性延长 Tlx 的表达导致成熟神经元的生成受损

作为成人神经发生动态过程的主要调节剂，孤儿核受体 Tailless (Tlx) 的及时表达和调节至关重要。然而，目前还没有研究直接研究精确时空表达的 Tlx 的重要作用。^{在这里，我们生成了 Tlx 表达转基因小鼠模型的条件增益，这允许通过与 TlxCreER T2}交配在神经干细胞 (NSC) 及其后代中扩展 Tlx 表达鼠标线。我们证明 Tlx 的扩展表达诱导成人脑室下区和颗粒下区成熟神经元的生成受损。此外，我们首次阐明了这种突变通过直接与其启动子结合来降低 Sox2 的内源性表达。恢复实验进一步证实，Sox2 部分挽救了这些神经元成熟缺陷。总之，这些发现不仅强调了按时关闭 Tlx 在控制 NSC 行为方面的重要性，而且还为进一步了解成人神经发生和制定神经系统疾病的治疗策略提供了见解。

更新日期：2021-07-16

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