The nonerythrocytic α-spectrin-1 (SPTAN1) gene encodes the cytoskeletal protein αII spectrin. Mutations in SPTAN1 cause early infantile epileptic encephalopathy type 5 (EIEE5); however, the role of αII spectrin in neurodevelopment and EIEE5 pathogenesis is unknown. Prior work suggests that αII spectrin is absent in the axon initial segment (AIS) and contributes to a diffusion barrier in the distal axon. Here, we have shown that αII spectrin is expressed ubiquitously in rodent and human somatodendritic and axonal domains. CRISPR-mediated deletion of Sptan1 in embryonic rat forebrain by in utero electroporation caused altered dendritic and axonal development, loss of the AIS, and decreased inhibitory innervation. Overexpression of human EIEE5 mutant SPTAN1 in embryonic rat forebrain and mouse hippocampal neurons led to similar developmental defects that were also observed in EIEE5 patient-derived neurons. Additionally, patient-derived neurons displayed aggregation of spectrin complexes. Taken together, these findings implicate αII spectrin in critical aspects of dendritic and axonal development and synaptogenesis, and support a dominant-negative mechanism of SPTAN1 mutations in EIEE5.

中文翻译：

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的关键作用α在大脑发育和癫痫性脑病II血影

非红细胞α-spectrin-1（SPTAN1）基因编码细胞骨架蛋白αII血影蛋白。SPTAN1中的突变会导致早期的5型婴儿癫痫性脑病（EIEE5）；然而，αII血影蛋白在神经发育和EIEE5发病机理中的作用尚不清楚。先前的工作表明，轴突起始节段（AIS）中不存在αII血影蛋白，并且有助于远端轴突的扩散屏障。在这里，我们已经证明，αII血影蛋白在啮齿动物和人的躯体树突状和轴突域中普遍存在。子宫内电穿孔的CRISPR介导的胚胎大鼠前脑Sptan1缺失导致树突状和轴突发育改变，AIS丧失和抑制神经支配减少。人EIEE5突变体的过表达SPTAN1在大鼠胚胎前脑和小鼠海马神经元中导致了进行了在EIEE5患者来源的神经元观察到了相似的发育缺陷。另外，患者来源的神经元显示血影蛋白复合物的聚集。综上所述，这些发现暗示αII血影蛋白在树突和轴突发育和突触形成的关键方面起作用，并支持EIEE5中SPTAN1突变的显性负性机制。