Disruption of TCF4 regulatory networks leads to abnormal cortical development and subsequent mental disabilities.
Disruption of TCF4 regulatory networks leads to abnormal cortical development and subsequent mental disabilities.
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TCF4 调节网络的破坏会导致皮质发育异常和随后的精神障碍。
作者：
Hong Li;Ying Zhu;Yury M. Morozov;Xiaoli Chen;Stephanie Cerceo Page;Matthew D. Rannals;Brady J. Maher;Pasko Rakic
TCF4基因在神经精神疾病的发生中所扮演的角色，是众多不同研究的主题。该基因已被确定为皮特-霍普金斯综合征(PTHS)的病因，并与其他各种神经精神疾病有关，包括精神分裂症、抑郁症和自闭症。然而，该基因参与神经发生，特别是皮质生成的确切分子机制还不是很清楚。在这里，我们提供的数据显示，TCF4在人类和小鼠早期妊娠的瞬时胚胎区的放射状胶质细胞和干细胞中以区域特异性的方式表达。TCF4单倍体缺陷小鼠表现出神经元迁移延迟，上层皮质神经元数量显著增加，树突和突触形成异常。我们的研究还发现，TCF3通过与TCF4基因内含子2中特定的E-box及其侧翼序列结合而上调TCF4。此外，我们的转录组研究证实，TCF4的转录功能对运动、认知和学习是必不可少的。通过激活TCF4的表达，调节神经元的增殖和迁移到覆盖的新皮质，随后的分化导致板层形成，TCF4完成了它的正常功能，但如果不是，就会导致像本文报道的那样的异常。这些发现为TCF4分子通路在新皮质发育中的具体作用及其在神经精神疾病发病机制中的相关性提供了新的见解。
The TCF4 gene is the subject of numerous and varied investigations of it’s role in the genesis of neuropsychiatric disease. The gene has been identified as the cause of Pitt-Hopkins Syndrome (PTHS) and it has been implicated in various other neuropsychiatric diseases, including schizophrenia, depression and autism. However, the precise molecular mechanisms of the gene’s involvement in neurogenesis, particularly, corticogenesis, are not well understood. Here, we present data showing that TCF4 is expressed in a region specific manner in the radial glia and stem cells of transient embryonic zones at early gestational ages in both humans and mice. TCF4 haploinsufficiency mice exhibit a delay in neuronal migration, and a significant increase in the number of upper-layer cortical neurons as well as abnormal dendrite and synapse formation. Our research also reveals that TCF3 up-regulates Tcf4 by binding to the specific “E-box” and its flank sequence in intron 2 of the Tcf4 gene. Additionally, our transcriptome study substantiates that Tcf4 transcriptional function is essential for locomotion, cognition and learning. By activating expression of TCF4 in the regulation of neuronal proliferation and migration to the overlaying neocortex and subsequent¬¬ differentiation leading to laminar formation TCF4 fulfills its normal function, but if not, abnormalities such as those reported here result. These findings provide new insight into the specific roles of Tcf4 molecular pathway in neocortical development and their relevance in the pathogenesis of neuropsychiatric disease.