PDF(Pubmed)
Abstract：
The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus-centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.
摘要：
大脑皮层的发育涉及一系列动态事件,包括细胞增殖和迁移，依赖于运动蛋白动力蛋白及其调节剂NDE1和NDEL1。虽然NDE1的功能丧失导致小头畸形相关的皮质发育（MCD）畸形，在MCD患者中未检测到NDEL1变体。这里,我们确定了两个有强直症的病人,有或没有皮质下频带异位症（SBH），携带相同的从头体细胞马赛克NDEL1变体，p.Arg105Pro（p.R105P)。通过单细胞RNA测序和空间转录组学分析，我们观察到Nde1/NDE1和Ndel1/NDEL1在神经祖细胞和有丝分裂后神经元中的互补表达，分别。子宫内电穿孔的Ndel1敲低导致神经元迁移受损，p.R105P无法挽救的表型值得注意的是,p.R105P单独表达强烈破坏神经元迁移，增加了领导过程的长度，核-中心体耦合受损，表明核动力失败。机械上,p.R105P破坏了NDEL1与动力蛋白调节因子LIS1的结合。这项研究确定了第一个与小脑相关的NDEL1变体，并揭示了NDE1和NDEL1在核动力和MCD发病机理中的不同作用。
