Three-dimensional regulation of radial glial functions by Lis1-Nde1 and dystrophin glycoprotein complexes.
Three-dimensional regulation of radial glial functions by Lis1-Nde1 and dystrophin glycoprotein complexes.
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DOI：
10.1371/journal.pbio.1001172
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发表时间：
2011-10
期刊：
影响因子：
9.8
通讯作者：
Feng Y
中科院分区：
文献类型：
--
作者：
Pawlisz AS;Feng Y
Lis 1-Nde 1通过稳定放射状胶质细胞的基底-外侧表面将大脑皮质神经发生与神经元迁移整合。放射状胶质细胞（Radial glial cells，RGC）是一类特殊的神经干细胞，具有极细长的双极形态，具有作为皮质神经元前体细胞和迁移支架的双重功能。在这里，我们展示了一种新的机制，通过这种机制，Lis 1-Nde 1复合物通过稳定抗肌萎缩蛋白/抗肌萎缩蛋白聚糖糖蛋白复合物（DGC）来维持RGC功能。Nde 1和utrophin/dystrophin之间的直接相互作用允许组装多蛋白复合物，该复合物将细胞骨架连接到RGC的细胞外基质，以稳定它们的侧膜、细胞-细胞粘附和放射状形态。Lis 1-Nde 1突变使DGC不稳定，并导致变形、脱节的RGC和破坏的基膜。除了受损的RGC自我更新和神经元迁移停滞外，Lis 1-Nde 1缺陷还导致神经元过度迁移。除了Lis 1-Nde 1与DGC的表型相似性之外，还发现Nde 1与RGC中的肌营养不良蛋白聚糖之间存在强的协同相互作用。由于LIS 1、NDE 1和dystroglycan的功能缺陷都导致无脑综合征，我们的数据表明，由Lis 1-Nde 1-DGC复合物对RGC细胞结构的三维调节决定了皮质神经元的数量和空间组织以及大脑皮质的大小和形状。发育中的大脑皮层内的神经发生和神经元迁移的过程必须紧密地协调，以使神经元有序地产生和运输到指定的皮层层。将这两个进程结合起来的机制仍然难以捉摸。放射状神经胶质细胞是发育中大脑中主要的神经干细胞，在皮层神经元迁移时既作为祖细胞又作为迁移支架。皮质发育性疾病无脑畸形（光滑脑）是神经发生和神经元迁移缺陷的结果，与蛋白质LIS 1及其结合伴侣NDE 1相关。在这项研究中，我们表明，在人类大脑皮层发育的几个关键球员，包括LIS 1，NDE 1，肌营养不良蛋白，肌营养不良蛋白聚糖，形成一个分子复合物，以调节皮质神经发生和神经元迁移的小鼠模型。这种多蛋白复合物在放射状胶质细胞的基底-外侧表面上是活跃的，已知其为迁移神经元提供指导。当我们在小鼠中耗尽NDE 1时，肌营养不良蛋白和肌营养不良蛋白聚糖从膜上丢失，放射状胶质细胞变形，表明多蛋白复合物对于适当的细胞形态的重要性。这种对形态学的影响导致了正常迁移和类似于无脑回畸形的皮质表型的丧失。我们的研究结果表明，基因调节的结构和功能的基底侧膜的放射状胶质细胞可能整合这些细胞的双重功能，并确定大脑皮层的大小，形状和功能。
Lis1-Nde1 integrates cerebral cortical neurogenesis with neuronal migration by stabilizing the basal-lateral surface of radial glial cells. Radial glial cells (RGCs) are distinctive neural stem cells with an extraordinary slender bipolar morphology and dual functions as precursors and migration scaffolds for cortical neurons. Here we show a novel mechanism by which the Lis1-Nde1 complex maintains RGC functions through stabilizing the dystrophin/dystroglycan glycoprotein complex (DGC). A direct interaction between Nde1 and utrophin/dystrophin allows for the assembly of a multi-protein complex that links the cytoskeleton to the extracellular matrix of RGCs to stabilize their lateral membrane, cell-cell adhesion, and radial morphology. Lis1-Nde1 mutations destabilized the DGC and resulted in deformed, disjointed RGCs and disrupted basal lamina. Besides impaired RGC self-renewal and neuronal migration arrests, Lis1-Nde1 deficiencies also led to neuronal over-migration. Additional to phenotypic resemblances of Lis1-Nde1 with DGC, strong synergistic interactions were found between Nde1 and dystroglycan in RGCs. As functional insufficiencies of LIS1, NDE1, and dystroglycan all cause lissencephaly syndromes, our data demonstrated that a three-dimensional regulation of RGC's cytoarchitecture by the Lis1-Nde1-DGC complex determines the number and spatial organization of cortical neurons as well as the size and shape of the cerebral cortex. The processes of neurogenesis and neuronal migration within the developing cerebral cortex must be tightly orchestrated to enable ordered generation and transportation of neurons to designated cortical layers. The mechanism by which these two processes are integrated remains elusive. Radial glial cells, the major neural stem cells in the developing brain, serve both as progenitors and migration scaffolds for cortical neurons as they migrate. The cortical developmental disease lissencephaly (smooth brain) is a result of defects in neurogenesis and neuronal migration, and is associated with the protein LIS1 and its binding partner NDE1. In this study, we show that several key players in human cerebral cortical development, including LIS1, NDE1, dystrophin, and dystroglycan, form a molecular complex to regulate cortical neurogenesis and neuronal migration in a mouse model. This multi-protein complex is active on the basal-lateral surface of radial glial cells, which is known to provide guidance to migrating neurons. When we depleted NDE1 in mice, dystrophin and dystroglycan were lost from the membrane and radial glial cells were deformed, indicating the importance of the multi-protein complex for proper cell morphology. This effect on morphology resulted in a loss of normal migration and cortical phenotypes similar to lissencephaly. Our findings suggest that genes that regulate the structure and function of the basal-lateral membrane of radial glial cells may integrate the dual functions of these cells and determine the size, shape, and function of the cerebral cortex.
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影响因子：
4.4
作者：
Lidov, HGW;Kunkel, LM
通讯作者：
Kunkel, LM
DOI：
10.1073/pnas.101122598
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2001-05-22
影响因子：
11.1
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影响因子：
21.3
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