The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation.
The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation.
复制标题
支架蛋白 Nde1 在早期神经祖细胞分化的 S 期保护大脑基因组。
作者：
Houlihan SL;Feng Y
成功完成每个细胞周期的S期可确保基因组的完整性。DNA复制障碍可导致DNA损伤和基因组疾病。在这项研究中，我们显示了一种新的功能NDE 1，其突变导致大脑发育障碍，在保护基因组通过S期在神经祖细胞命运限制性分化的早期步骤。Nde 1突变神经祖细胞表现出灾难性的DNA双链断裂与DNA复制的同时。这引起DNA损伤反应，导致p53依赖性细胞凋亡的激活，并导致皮质层II/III的神经元减少。我们发现了Nde 1的核库，确定了Nde 1与粘附素及其相关的染色质重塑的相互作用，并表明Nde 1突变体中停滞的DNA复制特异性地发生在异染色质结构域的中晚期S期。这些发现表明，NDE 1介导的异染色质复制是神经元分化不可或缺的，NDE 1功能的丧失可能导致基因组神经系统疾病。DOI：http://dx.doi.org/10.7554/eLife.03297.001大脑是一个复杂的器官，有许多不同的细胞类型，每种细胞都有专门的功能。控制大脑发育的基因突变可能会产生严重的后果，而与人类大脑发育有关的最重要的基因之一被称为NDE 1。从父母双方继承NDE 1基因突变拷贝的个体的大脑比健康大脑的褶皱更少，他们的大脑比正常人小90%。这些人可能有严重的发育障碍，挣扎于吞咽等基本功能，并过早死亡。此外，NDE 1基因的一个缺陷拷贝与白血病等癌症的发展有关。由NDE 1基因编码的蛋白质充当许多蛋白质复合物的支架，并且可以在整个细胞的各种细胞区室中（从细胞外周到细胞核）发现。然而，目前还不清楚NDE 1蛋白的活性在发育脑细胞中最需要的位置。Feng和Houlihan现在为NDE 1在大脑发育中的作用提供了新的解释。寻找与Nde 1蛋白的小鼠版本相互作用的分子显示，它与控制DNA如何在细胞核内包装的蛋白质结合。在这样做的过程中，Nde 1似乎保护了脑干细胞的基因组，而这些细胞的DNA在它们分裂形成注定成为神经元的新细胞之前被复制。为了使细胞分裂，它的遗传信息必须被准确地复制，然后在两个新细胞之间分离，以确保每个细胞都收到正常发育和功能所需的所有遗传指令。在没有功能性Nde 1的小鼠脑细胞中，DNA在复制时经常断裂。继承受损DNA的脑细胞可能无法正常工作，而影响DNA两条链的严重断裂可能会引发杀死突变细胞的反应。这意味着，构成大脑外层的细胞更少，使其比正常情况下皱纹更少。大脑的这一部分称为大脑皮层，对包括思维和记忆在内的许多过程都很重要，它帮助大脑的不同区域相互交流。这可以解释为什么NDE 1基因的突变可以导致各种脑部疾病。DNA复制过程中的错误也会导致癌症的发展。因此，Feng和Houlihan的发现也可能有助于解释为什么一些基因突变与癌症和大脑疾病有关。DOI：http://dx.doi.org/10.7554/eLife.03297.002网站
Successfully completing the S phase of each cell cycle ensures genome integrity. Impediment of DNA replication can lead to DNA damage and genomic disorders. In this study, we show a novel function for NDE1, whose mutations cause brain developmental disorders, in safeguarding the genome through S phase during early steps of neural progenitor fate restrictive differentiation. Nde1 mutant neural progenitors showed catastrophic DNA double strand breaks concurrent with the DNA replication. This evoked DNA damage responses, led to the activation of p53-dependent apoptosis, and resulted in the reduction of neurons in cortical layer II/III. We discovered a nuclear pool of Nde1, identified the interaction of Nde1 with cohesin and its associated chromatin remodeler, and showed that stalled DNA replication in Nde1 mutants specifically occurred in mid-late S phase at heterochromatin domains. These findings suggest that NDE1-mediated heterochromatin replication is indispensible for neuronal differentiation, and that the loss of NDE1 function may lead to genomic neurological disorders. DOI: http://dx.doi.org/10.7554/eLife.03297.001 The brain is a complex organ with many different cell types that each have specialized functions. Mutations in genes that control how the brain develops can have serious consequences—and one of the most important genes involved in the development of the human brain is called NDE1. Individuals who inherit mutated copies of the NDE1 gene from both parents have brains with fewer folds than a healthy brain, and their brains are up to 90% smaller than normal. These individuals may have serious developmental disabilities, struggle with basic functions like swallowing, and die early. Moreover, having just one defective copy of the NDE1 gene has been linked to the development of cancers such as leukemia. The protein encoded by the NDE1 gene acts as a scaffold for many protein complexes and can be found throughout the cell in various cellular compartments (from the cell periphery to the nucleus). However, it was unclear where the NDE1 protein's activity was most needed in developing brain cells. Feng and Houlihan now provide a new explanation for NDE1's role in brain development. Looking for molecules that interact with the mouse version of the Nde1 protein revealed that it binds to proteins that control how DNA is packaged inside the nucleus of a cell. In doing so, Nde1 appears to protect the genome of brain stem cells, while these cells' DNA is copied and before they divide to form new cells destined to become neurons. For a cell to divide, its genetic information must be accurately copied and then segregated between the two new cells to ensure that each receives all the genetic instructions needed to develop and function properly. In brain cells from mice without functional Nde1, the DNA frequently breaks as it is copied. Brain cells that inherit damaged DNA might not function correctly, while serious breaks that affect both strands of the DNA can trigger a response that kills the mutated cell. This means, there are fewer cells that make up the outer layer of the brain, making it less wrinkled than normal. This part of the brain—called the cerebral cortex—is important for many processes including thought and memory, and it helps different areas of the brain communicate with one another. This may explain why mutations in the NDE1 gene can contribute to a variety of brain disorders. Errors during DNA replication can also cause cancer to develop. As such, the findings of Feng and Houlihan may also help to explain why some genetic mutations are associated with both cancer and brain disorders. DOI: http://dx.doi.org/10.7554/eLife.03297.002