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Inhibition of Foxp4 Disrupts Cadherin-based Adhesion of Radial Glial Cells, Leading to Abnormal Differentiation and Migration of Cortical Neurons in Mice

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Abstract

Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders (NDDs) that exhibit delayed speech development, intellectual disability, and congenital abnormalities. The etiology of NDDs is unclear. Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells (RGCs), respectively, in the mouse neocortex during early gestation. Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone (VZ). Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ. The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs. The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions, the loss of which leads to periventricular heterotopias. We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.

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Acknowledgements

This work was supported by the Wenzhou Municipal Science and Technology Bureau (Y20210901), the Natural Science Foundation of Zhejiang Province (LQ20H090001), and the Scientific Research Fund of Wenling Science and Technology Bureau (2018C320001).

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Author notes

  1. Xue Li, Shimin Zou, and Xiaomeng Tu contributed equally to this work.

Authors and Affiliations

  1. School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China

    Xue Li, Shimin Zou, Xiaomeng Tu, Shishuai Hao & Jie-Guang Chen

  2. State Key Laboratory of Optometry, Ophthalmology and Vision Science, and Zhejiang Provincial Key Laboratory of Optometry and Ophthalmology, Wenzhou, 325027, China

    Xue Li, Shimin Zou, Xiaomeng Tu, Shishuai Hao & Jie-Guang Chen

  3. Research Center for Translational Medicine, the Affiliated Wenling Hospital of Wenzhou Medical University, Wenling, 317500, China

    Tian Jiang

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Li, X., Zou, S., Tu, X. et al. Inhibition of Foxp4 Disrupts Cadherin-based Adhesion of Radial Glial Cells, Leading to Abnormal Differentiation and Migration of Cortical Neurons in Mice. Neurosci. Bull. 39, 1131–1145 (2023). https://doi.org/10.1007/s12264-022-01004-7

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