Mutations of CNTNAP1 led to defects in neuronal development
Wanxing Li, … , Zilong Qiu, Wenhao Zhou
Wanxing Li, … , Zilong Qiu, Wenhao Zhou
Published November 5, 2020
Citation Information: JCI Insight. 2020;5(21):e135697. https://doi.org/10.1172/jci.insight.135697.
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Research Article Genetics Neuroscience

Mutations of CNTNAP1 led to defects in neuronal development

Abstract

Mutations of CNTNAP1 were associated with myelination disorders, suggesting the role of CNTNAP1 in myelination processes. Whether CNTNAP1 may have a role in early cortical neuronal development is largely unknown. In this study, we identified 4 compound heterozygous mutations of CNTNAP1 in 2 Chinese families. Using mouse models, we found that CNTNAP1 is highly expressed in neurons and is located predominantly in MAP2+ neurons during the early developmental stage. Importantly, Cntnap1 deficiency results in aberrant dendritic growth and spine development in vitro and in vivo, and it delayed migration of cortical neurons during early development. Finally, we found that the number of parvalbumin+ neurons in the cortex and hippocampus of Cntnap1–/– mice is strikingly increased by P15, suggesting that excitation/inhibition balance is impaired. Together, this evidence elucidates a critical function of CNTNAP1 in cortical development, providing insights underlying molecular and circuit mechanisms of CNTNAP1-related disease.

Authors

Wanxing Li, Lin Yang, Chuanqing Tang, Kaiyi Liu, Yulan Lu, Huijun Wang, Kai Yan, Zilong Qiu, Wenhao Zhou

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Figure 6

Cntnap1–/– mice showed delay migration and sparser dendrite branches.

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Cntnap1–/– mice showed delay migration and sparser dendrite branches. (...
(A and B) Representative images of coronal slices of E18.5 mouse brains transfected with shDsred at E13.5. At E18.5, KO cortical neurons showed a delay of migration compared with WT. Transfected cells were visualized by staining coronal slices with a GFP antibody. Scale bar: 500 μm. (C) Quantitative analysis of the distribution of cortical neurons from the ependyma to the pia mater (3 mice from each condition were randomly selected and measured). Statistical significance was evaluated by 1-way ANOVA. Data are shown as mean ± SEM. P = 0.1234 (ns). (D and E) Representative images of GFP-labeled cortical neurons in WT and KO mice by P10. We halved the plasmid concentration for sparse labeling. Scale bar: 100 μm. The neurite tracings of representative pyramidal neurons are shown on the right. (F and G) Quantification of the total dendrite length and the number of terminals of GFP labeled neurons. A total 20 and 19 neurons from WT and KO were randomly selected and measured. Statistical significance was evaluated by Student’s t test. Data are shown as mean ± SEM. P = 0.027 (E), P = 0.0462 (F). (H) Quantification of the dendritic branching of neurons collected at P10, as determined by Sholl analysis (20 and 19 neurons from each group were randomly selected and measured). P = 0.1234 (ns); ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05. Statistical significance was evaluated by 2-way ANOVA. Data are shown as mean ± SEM.