Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration.
Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration.
复制标题
NIPBL与ZFP609和Integrator复合物相互作用，以调节皮质神经元迁移。
DOI：
10.1016/j.neuron.2016.11.047
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发表时间：
2017-01-18
期刊：
影响因子：
16.2
通讯作者：
Guillemot F
中科院分区：
文献类型：
--
作者：
van den Berg DLC;Azzarelli R;Oishi K;Martynoga B;Urbán N;Dekkers DHW;Demmers JA;Guillemot F
NIPBL的突变是科尔内利亚德兰格综合征（CdLS）的最常见原因，CdLS是一种发育障碍，包括智力残疾和癫痫发作等多种神经缺陷。NIPBL突变如何影响大脑发育尚不清楚。在这里，我们确定Nipbl作为神经转录因子Zfp609在大脑发育中的功能相互作用伙伴。Zfp609或Nipbl在体内从皮质神经祖细胞中的耗尽对神经元迁移是有害的。Zfp609和Nipbl在基因组结合位点重叠，独立于粘着蛋白，并调节控制皮质神经元迁移的基因。我们发现Zfp609和Nipbl与整合子复合物相互作用，该复合物在RNA聚合酶2暂停释放中起作用。事实上，Zfp609和Nipbl共定位于含有暂停的RNA聚合酶2的基因启动子，并且Integrator类似地调节神经元迁移。我们的数据为Nipbl在与CdLS相关的神经缺陷中的作用提供了理论依据和机制见解。Nippl与转录因子Zfp 609和整合子复合体相互作用Nippl、Zfp 609和整合子是皮质神经元迁移所需的Nippl、Zfp 609和整合子共同占据基因组结合位点，独立于粘着蛋白Nippl、Zfp 609和整合子直接调节神经元迁移基因NIPBL突变导致科尔内利亚德兰格综合征，但NipBL在大脑发育中的功能尚不清楚。货车登贝格等人显示Nipbl与Zfp609和整合子复合物相互作用以转录调节皮质神经元迁移。
Mutations in NIPBL are the most frequent cause of Cornelia de Lange syndrome (CdLS), a developmental disorder encompassing several neurological defects, including intellectual disability and seizures. How NIPBL mutations affect brain development is not understood. Here we identify Nipbl as a functional interaction partner of the neural transcription factor Zfp609 in brain development. Depletion of Zfp609 or Nipbl from cortical neural progenitors in vivo is detrimental to neuronal migration. Zfp609 and Nipbl overlap at genomic binding sites independently of cohesin and regulate genes that control cortical neuron migration. We find that Zfp609 and Nipbl interact with the Integrator complex, which functions in RNA polymerase 2 pause release. Indeed, Zfp609 and Nipbl co-localize at gene promoters containing paused RNA polymerase 2, and Integrator similarly regulates neuronal migration. Our data provide a rationale and mechanistic insights for the role of Nipbl in the neurological defects associated with CdLS. Nipbl interacts with the transcription factor Zfp609 and the Integrator complex Nipbl, Zfp609, and Integrator are required for cortical neuron migration Nipbl, Zfp609, and Integrator co-occupy genomic binding sites independently of cohesin Nipbl, Zfp609, and Integrator directly regulate neuronal migration genes NIPBL mutations cause Cornelia de Lange syndrome, but Nipbl function in brain development is not well understood. Van den Berg et al. show that Nipbl interacts with Zfp609 and the Integrator complex to transcriptionally regulate cortical neuron migration.