An Autism-Related, Nonsense Foxp1 Mutant Induces Autophagy and Delays Radial Migration of the Cortical Neurons
An Autism-Related, Nonsense Foxp1 Mutant Induces Autophagy and Delays Radial Migration of the Cortical Neurons
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与自闭症相关的无意义 Foxp1 突变体诱导自噬并延迟皮质神经元的径向迁移
DOI：
10.1093/cercor/bhy185
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发表时间：
2019-07-01
期刊：
影响因子：
3.7
通讯作者：
Chen, Jie-Guang
中科院分区：
文献类型：
--
作者：
Li, Xue;Han, Xin;Chen, Jie-Guang
自闭症谱系障碍 (ASD) 是一种复杂的神经发育障碍，具有很强的遗传因素。 FOXP1（一种在发育中的大脑皮层中表达的转录因子）的破坏与 ASD 相关。 FOXP1(R525X)是在自闭症和严重智力低下患者中发现的一种从头杂合突变。为了探索 FOXP1(R525X) 在 ASD 中的神经元基础，我们创建了 Foxp1(R521X)，它是人类变体的小鼠同源物。 Foxp1(R521X) 的异位表达导致神经母细胞瘤 N2a 细胞和发育中的神经元细胞中的细胞质聚集并激活巨自噬。表达 Foxp1(R521X) 的皮质神经元表现出迁移延迟和树突形态改变。作为对照，在细胞质中扩散表达的突变体 Y435X 不会诱导皮质中的自噬和迁移延迟。通过剪接依赖性 NMD 报告基因检测，胚胎皮质细胞具有最小的无义介导的 mRNA 衰减 (NMD) 活性。我们假设发育中的神经元细胞使用自噬而不是 NMD 作为针对无义突变体聚集的保护机制，从而导致皮质发育受损。这项研究提出了除 FOXP1 杂合性缺失之外的 ASD 发展的新机制，并可能促进我们对基因突变与相关精神疾病之间复杂关系的理解。
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that has a strong genetic component. Disruptions of FOXP1, a transcription factor expressed in the developing cerebral cortex, were associated with ASD. FOXP1(R525X) is a de novo heterozygous mutation found in patients with autism and severe mental retardation. To explore the neuronal basis of FOXP1(R525X) in ASD, we created Foxp1(R521X), a mouse homolog of the human variant. Ectopic expression of Foxp1(R521X) led to cytoplasmic aggregates and activated macroautophagy in neuroblastoma N2a cells and the developing neuronal cells. Cortical neurons expressing Foxp1(R521X) exhibited delayed migration and altered dendritic morphology. As a control, mutant Y435X that was expressed diffusively in the cytoplasm did not induce autophagy and migration delay in the cortex. The embryonic cortical cells had a minimal activity of nonsense-mediated mRNA decay (NMD) as assayed by a splicing-dependent NMD reporter. We hypothesize that the developing neuronal cells use autophagy but not NMD as a safeguard mechanism against nonsense mutant aggregates, resulting in impairment of the cortical development. This study suggests a novel mechanism other than heterozygous loss of FOXP1 for the development of ASD and may advance our understanding of the complex relationships between gene mutation and the related psychiatric disorders.