Function of zinc finger protein 276 during CNS myelination and remyelination as part of the oligodendrocyte transcriptional network

锌指蛋白 276 在中枢神经系统髓鞘形成和髓鞘再生过程中作为少突胶质细胞转录网络一部分的功能

• 批准号: 398960687
• 负责人: Dr. Melanie Küspert
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398960687?language=en
• 关键词: Function; zinc; finger; protein; 276

Proper formation of myelin sheaths is a prerequisite for fast saltatory conduction and maintenance of axonal integrity in the vertebrate nervous system. Two types of myelin-forming glia, namely Schwann cells in the PNS and oligodendrocytes in the CNS, are responsible for establishing this structure and their differentiation is regulated by distinct transcriptional regulatory networks. In this project I will study the role of the yet uncharacterized transcription factor zinc finger protein 276 (Zfp276) during myelination and remyelination within the CNS. I identified this factor in recent transcriptome and ChIP-Seq experiments as a potential target of Sox10, one of the key transcriptional regulators of myelination in both CNS and PNS. Using histological, immunohistochemical, and ultrastructural techniques, I will perform detailed phenotypic analyses on CNS tissue of mice that carry an oligodendrocyte-specific deletion of the Zfp276 gene. Changes in remyelination capacities upon loss or gain of Zfp276 function will be studied using the organotypic slice culture system. I will complement these in vivo studies with data from primary oligodendroglial cultures to identify molecular functions of Zfp276 during oligodendroglial differentiation. Expression profiling and analyses of genomic occupancy of Zfp276 will identify regulatory targets and signaling pathways that mediate its function during oligodendroglial differentiation. Comparative analyses of my sequencing data with published RNA-Seq and ChIP-Seq data sets for major regulators of CNS myelination, such as Sox10 and Olig2, will help to integrate Zfp276 into the oligodendroglial transcriptional network and to identify upstream regulators as well as functional interactors.

髓鞘的正确形成是脊椎动物神经系统中快速跳跃传导和维持轴突完整性的先决条件。两种类型的髓鞘形成胶质细胞，即PNS中的Schwann细胞和CNS中的少突胶质细胞，负责建立这种结构，并且它们的分化受不同的转录调控网络的调控。在这个项目中，我将研究尚未表征的转录因子锌指蛋白276（Zfp 276）在中枢神经系统髓鞘形成和髓鞘再生过程中的作用。我在最近的转录组和ChIP-Seq实验中确定了这个因子作为Sox 10的潜在靶点，Sox 10是CNS和PNS髓鞘形成的关键转录调节因子之一。使用组织学，免疫组织化学和超微结构技术，我将进行详细的表型分析的中枢神经系统组织的小鼠携带少突胶质细胞特异性缺失的Zfp 276基因。将使用器官型切片培养系统研究Zfp 276功能丧失或获得后髓鞘再生能力的变化。我将补充这些在体内研究的数据，从原代少突胶质细胞培养，以确定在少突胶质细胞分化的分子功能Zfp 276。Zfp 276的基因组占用的表达谱分析和分析将确定在少突胶质细胞分化过程中介导其功能的调控靶点和信号通路。将我的测序数据与已发表的CNS髓鞘形成主要调控因子（如Sox 10和Olig 2）的RNA-Seq和ChIP-Seq数据集进行比较分析，将有助于将Zfp 276整合到少突胶质细胞转录网络中，并确定上游调控因子以及功能相互作用因子。