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 diseases.

TCF4 基因是其在神经精神疾病发生中的作用的众多研究的主题。该基因已被确定为皮特-霍普金斯综合征（PTHS）的病因，并且与多种其他神经精神疾病有关，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，特别是皮质发生的精确分子机制尚不清楚。在这里，我们提供的数据显示，TCF4 在人类和小鼠妊娠早期瞬时胚胎区的放射状胶质细胞和干细胞中以区域特异性方式表达。 TCF4单倍体不足的小鼠表现出神经元迁移延迟、上层皮质神经元数量显着增加以及异常树突和突触形成。我们的研究还表明，TCF3 通过与Tcf4基因内含子 2 中的特定“E-box”及其侧翼序列结合来上调Tcf4 。此外，我们的转录组研究证实Tcf4转录功能对于运动、认知和学习至关重要。通过激活 TCF4 的表达来调节神经元增殖和迁移到覆盖的新皮质以及随后导致层状形成的分化，TCF4 实现其正常功能，但如果不能，则会导致本文报道的异常。这些发现为Tcf4分子通路在新皮质发育中的具体作用及其与神经精神疾病发病机制的相关性提供了新的见解。