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

Molecular Psychiatry volume 26, pages 6562–6577 (2021)Cite this article

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Abstract

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.

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Fig. 1: Tcf4 is required for neuronal positioning.
Fig. 2: Tcf4-deficient neurons migrate to the cortical plate.
Fig. 3: Abnormal positioning of Tcf4-deficient neurons.
Fig. 4: Neurons become clustered upon the loss of Tcf4.
Fig. 5: Tcf4 acts through Fn1 to regulate neuronal positioning.
Fig. 6: Disruption of the neuronal function upon the loss of Tcf4.

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Acknowledgements

We thank all members of the Xie lab for discussions. We thank Drs. T. Behnish and Y. Jiang for critical reading the manuscript. We thank the IOBS Core facility for expert microscopy. This study was supported by the National Key Research and Development Program of China (grant no. 2018YFA0108000), the National Natural Science Foundation of China (grant nos. 31872763, 31471038, 81828008), Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01, 19JC1411003) and ZJLab to YX and the National Natural Science Foundation of China (grant nos. 31872764, 81800862), Shanghai Science and Technology Committee (grant no. 19QA1401600) to YG, Shanghai Pujiang Program (19PJ1401800) to LX.

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Authors and Affiliations

  1. Department of Anesthesia, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, and Zhongshan Hospital, Fudan University, Shanghai, China

    Yandong Zhang, Zheping Cai, Guanglei Hu, Songhui Hu, Yafei Wang, Na Li, Saiyong Chen, Qiong Liu, Lanhui Zeng, Tianxiang Tang, Yilan Zhang, Lei Xiao, Yu Gu & Yunli Xie

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  1. Yandong Zhang
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YX conceived and designed the project. Yandong Z performed experiments and analyzed the data with help from CZ, WY, LZ, Yilan Z, and TT, GH, NL, QL, and YG performed and analyzed in vivo recording experiments. SH, SC, and LX performed and analyzed in vitro recording experiments. YX performed experiments, analyzed the data, and wrote the manuscript with comments from other authors.

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Correspondence to Yunli Xie.

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Zhang, Y., Cai, Z., Hu, G. et al. Transcription factor 4 controls positioning of cortical projection neurons through regulation of cell adhesion. Mol Psychiatry 26, 6562–6577 (2021). https://doi.org/10.1038/s41380-021-01119-9

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