Subcortical heterotopia is a cortical malformation associated with epilepsy, intellectual disability, and an excessive number of cortical neurons in the white matter. Echinoderm microtubule-associated protein like 1 (EML1) mutations lead to subcortical heterotopia, associated with abnormal radial glia positioning in the cortical wall, prior to malformation onset. This perturbed distribution of proliferative cells is likely to be a critical event for heterotopia formation; however, the underlying mechanisms remain unexplained. This study aimed to decipher the early cellular alterations leading to abnormal radial glia. In a forebrain conditional Eml1 mutant model and human patient cells, primary cilia and centrosomes are altered. Microtubule dynamics and cell cycle kinetics are also abnormal in mouse mutant radial glia. By rescuing microtubule formation in Eml1 mutant embryonic brains, abnormal radial glia delamination and heterotopia volume were significantly reduced. Thus, our new model of subcortical heterotopia reveals the causal link between Eml1's function in microtubule regulation and cell position, both critical for correct cortical development.

中文翻译：

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前脑 Eml1 耗竭揭示了早期中心体功能障碍，导致皮质下异位。


皮质下异位是一种与癫痫、智力障碍和白质中皮质神经元过多相关的皮质畸形。棘皮动物微管相关蛋白样 1 (EML1) 突变导致皮质下异位，与畸形发生前皮质壁中放射状胶质细胞的异常定位有关。增殖细胞的这种扰动分布可能是异位形成的关键事件。然而，其根本机制仍不清楚。这项研究旨在破译导致异常放射状胶质细胞的早期细胞改变。在前脑条件 Eml1 突变模型和人类患者细胞中，初级纤毛和中心体发生了改变。小鼠放射状胶质细胞突变体的微管动力学和细胞周期动力学也异常。通过挽救 Eml1 突变体胚胎大脑中的微管形成，异常的放射状胶质分层和异位体积显着减少。因此，我们的新皮质下异位模型揭示了 Eml1 的微管调节功能和细胞位置之间的因果关系，这两者对于正确的皮质发育都至关重要。