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

• Published in: Molecular psychiatry Vol. 26; no. 11; pp. 6562 - 6577
• Main Authors: Zhang, Yandong, Cai, Zheping, Hu, Guanglei, Hu, Songhui, Wang, Yafei, Li, Na, Chen, Saiyong, Liu, Qiong, Zeng, Lanhui, Tang, Tianxiang, Zhang, Yilan, Xiao, Lei, Gu, Yu, Xie, Yunli
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2021
• Subjects: Brain research; Causes of; Cell Adhesion; Cell adhesion & migration; Cell adhesion molecules; Cellular control mechanisms; Central nervous system diseases; Cerebral cortex; Child development deviations; Developmental disabilities; Electrophysiology; Facies; Health aspects; Humans; Hyperventilation - genetics; Hyperventilation - metabolism; Intellectual disabilities; Intellectual Disability - genetics; Localization; Mental disorders; Mutation; Neural circuitry; Neural networks; Neurons; Neurons - metabolism; Physiological aspects; Schizophrenia; Transcription Factor 4 - genetics; Transcription Factor 4 - metabolism; Transcription factors; China
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-021-01119-9

The establishment of neural circuits depends on precise neuronal positioning in the cortex, which occurs via a tightly coordinated process of neuronal differentiation, migration, and terminal localization. Deficits in this process have been 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 but also provide new insights into the potential mechanisms underlying neurological defects linked to TCF4 mutations.