Rbfox Splicing Factors Promote Neuronal Maturation and Axon Initial Segment Assembly.,Neuron

当前位置： X-MOL 学术 › Neuron › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Rbfox Splicing Factors Promote Neuronal Maturation and Axon Initial Segment Assembly.
Neuron ( IF 14.7 ) Pub Date : 2018-Feb-21 , DOI: 10.1016/j.neuron.2018.01.020
Martin Jacko ₁ , Sebastien M Weyn-Vanhentenryck ₂ , John W Smerdon ₃ , Rui Yan ₄ , Huijuan Feng ₅ , Damian J Williams ₆ , Joy Pai ₂ , Ke Xu ₄ , Hynek Wichterle ₇ , Chaolin Zhang ₂

Affiliation

Departments of Systems Biology and Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Departments of Pathology and Cell Biology, Neurology, and Neuroscience, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA.
Departments of Systems Biology and Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Departments of Pathology and Cell Biology, Neurology, and Neuroscience, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
Departments of Systems Biology and Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST/Department of Automation, Tsinghua University, Beijing 100084, China.
Columbia University Stem Cell Core Facility, Department of Rehabilitation and Regenerative Medicine, New York, NY 10032, USA.
Departments of Pathology and Cell Biology, Neurology, and Neuroscience, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA.

Neuronal maturation requires dramatic morphological and functional changes, but the molecular mechanisms governing this process are not well understood. Here, we studied the role of Rbfox1, Rbfox2, and Rbfox3 proteins, a family of tissue-specific splicing regulators mutated in multiple neurodevelopmental disorders. We generated Rbfox triple knockout (tKO) ventral spinal neurons to define a comprehensive network of alternative exons under Rbfox regulation and to investigate their functional importance in the developing neurons. Rbfox tKO neurons exhibit defects in alternative splicing of many cytoskeletal, membrane, and synaptic proteins, and display immature electrophysiological activity. The axon initial segment (AIS), a subcellular structure important for action potential initiation, is diminished upon Rbfox depletion. We identified an Rbfox-regulated splicing switch in ankyrin G, the AIS "interaction hub" protein, that regulates ankyrin G-beta spectrin affinity and AIS assembly. Our data show that the Rbfox-regulated splicing program plays a crucial role in structural and functional maturation of postmitotic neurons.

中文翻译：

Rbfox 剪接因子促进神经元成熟和轴突初始片段组装。

神经元的成熟需要显着的形态和功能变化，但控制这一过程的分子机制尚不清楚。在这里，我们研究了 Rbfox1、Rbfox2 和 Rbfox3 蛋白的作用，它们是在多种神经发育障碍中突变的组织特异性剪接调节因子家族。我们生成了 Rbfox 三重敲除 (tKO) 腹侧脊髓神经元，以定义 Rbfox 调节下的替代外显子的综合网络，并研究它们在神经元发育中的功能重要性。 Rbfox tKO 神经元在许多细胞骨架、膜和突触蛋白的选择性剪接中表现出缺陷，并表现出不成熟的电生理活性。轴突起始段 (AIS) 是一种对动作电位启动很重要的亚细胞结构，在 Rbfox 耗尽时会减少。我们在锚蛋白 G（AIS“相互作用中心”蛋白）中发现了 Rbfox 调节的剪接开关，它调节锚蛋白 G-β 血影蛋白亲和力和 AIS 组装。我们的数据表明，Rbfox 调节的剪接程序在有丝分裂后神经元的结构和功能成熟中发挥着至关重要的作用。

更新日期：2018-02-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11