Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.

中文翻译：

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lissencephaly的体外模型：扩展DCX在神经发生过程中的作用。

缺脑畸形包括由于发育中的大脑皮层神经元迁移受损而引起的一系列脑畸形。古典性脑小脑畸形的特征在于光滑的脑表面和皮质增厚，导致癫痫发作，严重的神经系统损伤和发育延迟。编码双皮质素的X染色体基因DCX中的突变是经典性脑小脑畸形的主要原因。我们对DCX相关的脑性脑病的很多知识来自对患者大脑的事后分析，这主要是因为具有DCX突变的动物模型不能模仿这种疾病。在缺乏相关动物模型和患者脑标本的情况下，我们利用诱导多能干细胞（iPSC）技术对疾病进行建模。我们从具有突变DCX和经典lissencephaly，包括光滑的大脑和异常的皮层形态的两名男性建立了人类iPSC。通过将iPSC分化为神经细胞，然后进行表达谱分析和解剖DCX相关功能，可以概括该疾病。在这里，我们显示了神经干细胞，缺少或减少了DCX蛋白的表达，显示出受损的迁移，延迟的分化和不足的神经突形成。因此，患者来源的iPSC和神经干细胞提供了进一步揭示DCX在正常发育和疾病中的功能的系统。DCX蛋白表达缺失或减少的人，其迁移能力受损，分化延迟和神经突形成不足。因此，患者来源的iPSC和神经干细胞提供了进一步揭示DCX在正常发育和疾病中的功能的系统。DCX蛋白表达缺失或减少的人，其迁移能力受损，分化延迟和神经突形成不足。因此，患者来源的iPSC和神经干细胞提供了进一步揭示DCX在正常发育和疾病中的功能的系统。