KCC2, encoded in humans by the SLC12A5 gene, is a multifunctional neuron-specific protein initially identified as the chloride (Cl- ) extruder critical for hyperpolarizing GABAA receptor currents. Independently of its canonical function as a K-Cl cotransporter, KCC2 regulates the actin cytoskeleton via molecular interactions mediated through its large intracellular C-terminal domain (CTD). Contrary to the common assumption that embryonic neocortical projection neurons express KCC2 at non-significant levels, here we show that loss of KCC2 enhances apoptosis of late-born upper-layer cortical projection neurons in the embryonic brain. In utero electroporation of plasmids encoding truncated, transport-dead KCC2 constructs retaining the CTD was as efficient as of that encoding full-length KCC2 in preventing elimination of migrating projection neurons upon conditional deletion of KCC2. This was in contrast to the effect of a full-length KCC2 construct bearing a CTD missense mutation (KCC2R952H ), which disrupts cytoskeletal interactions and has been found in patients with neurological and psychiatric disorders, notably seizures and epilepsy. Together, our findings indicate ion transport-independent, CTD-mediated regulation of developmental apoptosis by KCC2 in migrating cortical projection neurons.

中文翻译：

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非经典 KCC2 功能的丧失促进了皮质投射神经元的发育凋亡。

KCC2 在人类中由 SLC12A5 基因编码，是一种多功能神经元特异性蛋白质，最初被鉴定为对 GABAA 受体电流超极化至关重要的氯化物 (Cl-) 挤出物。独立于其作为 K-Cl 协同转运蛋白的典型功能，KCC2 通过其大细胞内 C 末端结构域 (CTD) 介导的分子相互作用调节肌动蛋白细胞骨架。与胚胎新皮质投射神经元以非显着水平表达 KCC2 的普遍假设相反，我们在此显示 KCC2 的缺失增强了胚胎大脑中晚出生的上层皮质投射神经元的细胞凋亡。在子宫内电穿孔编码截短的质粒，保留 CTD 的运输死亡 KCC2 结构与编码全长 KCC2 的结构一样有效，可防止在条件性删除 KCC2 时消除迁移的投射神经元。这与带有 CTD 错义突变 (KCC2R952H) 的全长 KCC2 构建体的效果形成对比，后者破坏了细胞骨架相互作用，并且已在患有神经和精神疾病，特别是癫痫发作和癫痫症的患者中发现。总之，我们的研究结果表明，KCC2 在迁移的皮质投射神经元中不依赖于离子转运、CTD 介导的发育凋亡调节。它破坏了细胞骨架的相互作用，并且已在患有神经和精神疾病，特别是癫痫发作和癫痫的患者中发现。总之，我们的研究结果表明，KCC2 在迁移的皮质投射神经元中不依赖于离子转运、CTD 介导的发育凋亡调节。它破坏了细胞骨架的相互作用，并且已在患有神经和精神疾病，特别是癫痫发作和癫痫的患者中发现。总之，我们的研究结果表明，KCC2 在迁移的皮质投射神经元中不依赖于离子转运、CTD 介导的发育凋亡调节。