Tcf3 represses Wnt-β-catenin signaling and maintains neural stem cell population during neocortical development.
Tcf3 represses Wnt-β-catenin signaling and maintains neural stem cell population during neocortical development.
复制标题
Tcf3可抑制Wnt-β-catenin信号，并在新皮质发育过程中维持神经干细胞的数量。
DOI：
10.1371/journal.pone.0094408
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Gotoh Y
中科院分区：
文献类型：
--
作者：
Kuwahara A;Sakai H;Xu Y;Itoh Y;Hirabayashi Y;Gotoh Y
在小鼠新皮质发育过程中，Wnt-β-连环蛋白信号通路在神经元分化和神经前体细胞（NPC）增殖等多种现象中发挥着重要作用。在不消耗 NPC 群体的情况下产生适当数量的神经元需要精确调节 NPC 的分化和维持之间的平衡。然而，抑制 Wnt 信号传导以防止 NPC 神经元过早分化的机制尚不清楚。我们现在证明 HMG 盒转录因子 Tcf3（也称为 Tcf7l1）有助于这种机制。 Tcf3 在小鼠新皮质的未分化 NPC 中高度表达，而其表达在决定神经元命运的中间神经元祖细胞 (INP) 中降低。我们在报告基因检测中发现 Tcf3 是新皮质 NPC 中 Wnt 信号传导的抑制因子。 Tcf3 与原神经 bHLH 基因 Neurogenin1 (Neurog1) 的启动子结合并抑制其表达。与此一致的是，Tcf3 抑制神经元分化并增加 NPC 的自我更新活性。我们还发现，Wnt 信号刺激会降低 NPC 中 Tcf3 的水平，并增加 Tcf1（也称为 Tcf7）和 Lef1（Wnt 信号传导的正介体）的水平。总之，这些结果表明 Tcf3 拮抗 NPC 中的 Wnt 信号传导，从而维持其在新皮质中的未分化状态，并且 Wnt 信号传导促进从 Tcf3 介导的抑制向 Tcf1/Lef1 介导的 Wnt 信号传导增强的转变，构成促进神经元分化的正反馈回路。
During mouse neocortical development, the Wnt–β-catenin signaling pathway plays essential roles in various phenomena including neuronal differentiation and proliferation of neural precursor cells (NPCs). Production of the appropriate number of neurons without depletion of the NPC population requires precise regulation of the balance between differentiation and maintenance of NPCs. However, the mechanism that suppresses Wnt signaling to prevent premature neuronal differentiation of NPCs is poorly understood. We now show that the HMG box transcription factor Tcf3 (also known as Tcf7l1) contributes to this mechanism. Tcf3 is highly expressed in undifferentiated NPCs in the mouse neocortex, and its expression is reduced in intermediate neuronal progenitors (INPs) committed to the neuronal fate. We found Tcf3 to be a repressor of Wnt signaling in neocortical NPCs in a reporter gene assay. Tcf3 bound to the promoter of the proneural bHLH gene Neurogenin1 (Neurog1) and repressed its expression. Consistent with this, Tcf3 repressed neuronal differentiation and increased the self-renewal activity of NPCs. We also found that Wnt signal stimulation reduces the level of Tcf3, and increases those of Tcf1 (also known as Tcf7) and Lef1, positive mediators of Wnt signaling, in NPCs. Together, these results suggest that Tcf3 antagonizes Wnt signaling in NPCs, thereby maintaining their undifferentiated state in the neocortex and that Wnt signaling promotes the transition from Tcf3-mediated repression to Tcf1/Lef1-mediated enhancement of Wnt signaling, constituting a positive feedback loop that facilitates neuronal differentiation.
登录
查看更多内容
影响因子：
10.5
作者：
Cole, Megan F.;Johnstone, Sarah E.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
4
作者：
Hoppler, Stefan;Kavanagh, Claire Louise
通讯作者：
Kavanagh, Claire Louise
影响因子：
2.9
作者：
Hirabayashi, Y;Gotoh, Y
通讯作者：
Gotoh, Y
影响因子：
16.2
作者：
Hirabayashi, Yusuke;Suzki, Nao;Gotoh, Yukiko
通讯作者：
Gotoh, Yukiko
影响因子：
21.3
作者：
Kaykas, A;Yang-Snyder, J;Moon, RT
通讯作者：
Moon, RT