Epigenetic Regulation of Mode of cortical Interneuron Migration

皮质中间神经元迁移模式的表观遗传调控

• 批准号: 464321698
• 负责人: Professorin Dr. Geraldine Zimmer-Bensch
• 金额: --
• 依托单位: Abteilung Functional Epigenetics in the animal model
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/464321698?language=en
• 关键词: Epigenetic; Regulation; Mode; cortical; Interneuron

Understanding the cellular and molecular mechanisms that govern the timely ordered developmental processes during brain unfolding like neuronal differentiation and migration, is a fundamental goal in neuroscience. The different steps of neuronal maturation rely on stage-specific gene expression programs, which are modulated by local environmental stimuli. This becomes clearly evident for the migration of inhibitory GABAergic cortical interneurons from their sites of origin within the basal telencephalon to their final cortical target regions. After tangentially spreading over the different cortical areas, interneurons switch to a radial mode of migration to invade the cortical layers. These different steps are modulated by secreted or membrane-bound proteins, which trigger stage-specific gene expression programs that direct the physiological responses such as cytoskeletal remodeling. To decipher the interplay of environmental signals and transcriptional programs underlying this switch in migration mode is critical, as its timing defines the final interneuron number in a given cortical area. Understanding these processes and signaling networks is prerequisite to approach the etiology of neuropsychiatric diseases like schizophrenia and epilepsy, as such disorders at least in part rely on defective development and distribution of inhibitory GABAergic interneurons. Epigenetic gene regulatory mechanisms, such as DNA methylation, histone modification and non-coding RNAs, seem to play a key role in integrating stimuli from the local microenvironment into the genome, thereby influencing stage-specific transcriptional networks. However, so far little is known about discrete epigenetic profiles in setting up stage-specific transcriptional programs in cortical interneurons, and how they can be shaped by external signals.In preliminary studies we provided evidence that the DNA methyltransferase 1 (DNMT1) regulates stage-specific gene expression in migrating cortical interneurons. Further, we found that DNMT1 binding to specific gene loci and to particular lncRNAs can be altered upon external stimulation with an important regulatory membrane protein. This fits to the proposed function of lncRNAs in targeting DNA methylation. Based on these data, we here will address the role of stage-specific DNMT1-dependent DNA methylation for instructing transcriptional networks that direct the tangential to radial switch of cortical interneuron migration. We further ask, whether DNMT1 targeting depends on changing microenvironment and lncRNA function. To this end, we will apply a battery of innovative methods including mouse genetics, high-throughput sequencing of cortical interneurons, and sophisticated in vivo and in vitro functional validation approaches. Besides contributing to the understanding of neuropsychiatric disease etiology, this project will set the basis to develop epigenetic-based therapy strategies on the long run.

了解在大脑发育过程中控制神经元分化和迁移的细胞和分子机制是神经科学的一个基本目标。神经元成熟的不同步骤依赖于阶段特异性基因表达程序，这些程序受局部环境刺激的调节。这对于抑制性GABA能皮质中间神经元从其基底端脑内的起源部位迁移到其最终皮质靶区域变得明显。在切向分布在不同的皮质区域之后，中间神经元切换到径向迁移模式以侵入皮质层。这些不同的步骤由分泌的或膜结合的蛋白质调节，这些蛋白质触发阶段特异性基因表达程序，指导生理反应，如细胞骨架重塑。破译迁移模式中这种转换背后的环境信号和转录程序的相互作用至关重要，因为其时间决定了给定皮层区域中最终的中间神经元数量。了解这些过程和信号网络是探讨精神分裂症和癫痫等神经精神疾病病因的先决条件，因为这些疾病至少部分依赖于抑制性GABA能中间神经元的发育和分布缺陷。表观遗传基因调控机制，如DNA甲基化，组蛋白修饰和非编码RNA，似乎在将局部微环境的刺激整合到基因组中，从而影响阶段特异性转录网络中发挥关键作用。然而，到目前为止，很少有人知道离散的表观遗传配置文件在建立阶段特异性转录程序在皮层interneurons，以及它们如何可以塑造外部signals.In初步研究中，我们提供的证据表明，DNA甲基转移酶1（DNMT1）调节阶段特异性基因表达迁移皮层interneurons。此外，我们发现，DNMT1结合到特定的基因位点和特定的lncRNA可以改变后，外部刺激与一个重要的调节膜蛋白。这符合lncRNA在靶向DNA甲基化中的拟议功能。基于这些数据，我们将在这里解决的作用，阶段特异性DNMT1依赖的DNA甲基化指导转录网络，直接切向径向开关皮层中间神经元迁移。我们进一步询问，DNMT1靶向是否取决于改变微环境和lncRNA功能。为此，我们将应用一系列创新方法，包括小鼠遗传学，皮质中间神经元的高通量测序，以及复杂的体内和体外功能验证方法。除了有助于了解神经精神疾病的病因，这个项目将奠定基础，发展表观遗传学为基础的治疗策略，从长远来看。