Transcription factor 4 controls positioning of cortical projection neurons through regulation of cell adhesion. Transcription factor 4 controls positioning of cortical projection neurons through regulation of cell adhesion

The establishment of neural circuits depends on precise neuronal positioning in the cortex, a tightly coordinated process of neuronal differentiation, migration and terminal localization. Deficit in this process is implicated in several psychiatric disorders. Here, we show that the transcription factor Tcf4 controls neuronal positioning during brain development. Tcf4-deficient neurons become mispositioned in clusters when their migration to the cortical plate is complete. We reveal that Tcf4 regulates the expression of cell adhesion molecules to control neuronal positioning. Furthermore, through in vivo extracellular electrophysiology, we show that neuronal functions are disrupted after the loss of Tcf4. TCF4 mutations are strongly associated with schizophrenia and cause Pitt-Hopkins syndrome, which is characterized by severe intellectual disability. Thus, our results not only reveal the importance of neuronal positioning in brain development and but also provide new insights into the potential mechanisms underlying neurological defects linked to TCF4 mutations. Overall design: examine the gene expression change after loss of TCf4

神经环路的建立依赖于大脑皮层中神经元的精准定位，这是一个受严格调控的神经元分化、迁移及终末定位过程。该过程的功能异常与多种精神疾病密切相关。本研究证实，转录因子Tcf4 (transcription factor Tcf4) 在大脑发育过程中调控神经元定位。当神经元迁移至皮质板完成后，Tcf4缺陷型神经元会以簇状形式出现定位异常。我们揭示Tcf4通过调控细胞黏附分子的表达来控制神经元定位。此外，通过在体细胞外电生理实验，我们证实Tcf4缺失后神经元功能会受到破坏。TCF4突变与精神分裂症密切相关，且会引发皮特-霍普金斯综合征，该病症以重度智力障碍为特征。因此，本研究结果不仅揭示了神经元定位在大脑发育中的重要性，还为阐释TCF4突变相关神经缺陷的潜在分子机制提供了新视角。实验设计概述：探究Tcf4缺失后的基因表达变化。