Contactin 4 (CNTN4) is a crucial synaptic adhesion protein that belongs to the contactin superfamily. Evidence from both human genetics and mouse models suggests that synapse formation and structural deficits strongly correlate with neurodevelopmental disorders, including autism. In addition, several lines of evidence suggest that CNTN4 is associated with the risk of autism. However, the biological functions of CNTN4 in neural development and disease pathogenesis are poorly understood. In this study, we investigated whether and how CNTN4 is autonomously involved in the development of dendrites and dendritic spines in cortical neurons. Disruption of Cntn4 decreased the number of excitatory synapses, which led to a reduction in neural activity. Truncated proteins lacking the signal peptide, FnIII domains or GPI domain lacked the ability to regulate dendritic spine formation, indicating that CNTN4 regulates dendritic spine density through a mechanism dependent on FnIII domains. Importantly, we revealed that autism-related variants lacked the ability to regulate spine density and neural activity. In conclusion, our study suggests that CNTN4 is essential for promoting dendrite growth and dendritic spine formation and that disruptive variants of CNTN4 interfere with abnormal synapse formation and may increase the risk of autism.

中文翻译：

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自闭症风险基因 CNTN4 调节树突棘的形成

Contactin 4 (CNTN4) 是一种重要的突触粘附蛋白，属于contactin 超家族。来自人类遗传学和小鼠模型的证据表明，突触形成和结构缺陷与包括自闭症在内的神经发育障碍密切相关。此外，多条证据表明 CNTN4 与自闭症风险相关。然而，人们对 CNTN4 在神经发育和疾病发病机制中的生物学功能知之甚少。在这项研究中，我们研究了 CNTN4 是否以及如何自主参与皮层神经元中树突和树突棘的发育。Cntn4 的破坏减少了兴奋性突触的数量，从而导致神经活动减少。缺乏信号肽的截短蛋白质，FnIII结构域或GPI结构域缺乏调节树突棘形成的能力，表明CNTN4通过依赖于FnIII结构域的机制调节树突棘密度。重要的是，我们发现自闭症相关变异缺乏调节脊柱密度和神经活动的能力。总之，我们的研究表明 CNTN4 对于促进树突生长和树突棘形成至关重要，并且 CNTN4 的破坏性变体会干扰异常突触形成并可能增加自闭症的风险。