The histone methyltransferase DOT1L impacts interneuron localisation and maturation in the cerebral cortex and hippocampus

组蛋白甲基转移酶 DOT1L 影响大脑皮层和海马的中间神经元定位和成熟

• 批准号: 328525752
• 负责人: Professorin Dr. Tanja Vogel
• 金额: --
• 依托单位: Anatomie II: Abteilung für Molekulare Embryologie
• 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/328525752?language=en
• 关键词: histone; methyltransferase; DOT1L; impacts; interneuron

The cortical plate is composed of excitatory and inhibitory neurons, the latter of which originate in the ganglionic eminences. From their origin in the ventral telencephalon interneuron precursors migrate during embryonic development over large distance to reach their final destination in the cortical plate. The histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, and affects interneuron development in both a cell-autonomous and non-autonomous manner. Deletion of DOT1L in medial ganglionic eminence (MGE)-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate mostly affecting Parvalbumin (PVALB)-expressing interneurons. Our findings suggest that reduced numbers of cortical interneurons upon DOT1L deletion results from altered postmitotic differentiation/maturation. However, the diversity and spatio-temporal differences in cell fate determining cues acting on interneurons requires higher resolution through single cell (sc) RNA- and ATAC-seq to fully acknowledge the impact of DOT1L on cortical interneurons. We propose to use scRNA-, scATAC- and scCUT&TAG to resolve transcriptomic alterations and underlying molecular mechanisms in DOT1L mutant mouse forebrains and in depth exploration of cell-autonomous effects of altered epigenetic information. In addition, we observed cell non-autonomous developmental defects of the interneuron lineage through loss of DOT1L within the glutamatergic lineage. We propose to extend scRNA- and scATAC-data to further developmental time points and to analyse in depth signaling pathways that originate from glutamatergic neurons that impact numbers of interneurons in the developing cortical plate. Together, this project will enlighten one epigenetic mechanisms that contributes to balance numbers of glutamatergic and GABAergic neurons in the cerebral cortex. Understanding this basic developmental principle is of major importance to evaluate whether epigenetics is a means to prevent or treat for example psychiatric diseases associated with impaired excitatory/inhibitory information processing.

皮质板由兴奋性和抑制性神经元组成，后者起源于神经节隆起。中间神经元前体在胚胎发育过程中从腹侧端脑的起源迁移很长一段距离，到达皮质板中的最终目的地。组蛋白甲基转移酶DOT 1 L是必要的适当的皮质板的发展和层分布的海马神经元，并影响interneuron的发展，在两个细胞自主和非自主的方式。在内侧神经节隆起（MGE）衍生的中间神经元前体细胞中DOT 1 L的缺失导致皮质板中GABA能中间神经元的总体减少和分布改变，主要影响小清蛋白（PVALB）表达的中间神经元。我们的研究结果表明，DOT 1 L缺失后皮质中间神经元的数量减少是由有丝分裂后分化/成熟的改变引起的。然而，作用于中间神经元的细胞命运决定线索的多样性和时空差异需要通过单细胞（sc）RNA-和ATAC-seq的更高分辨率，以充分认识DOT 1 L对皮质中间神经元的影响。我们建议使用scRNA-，scATAC-和scCUT&TAG来解决DOT 1 L突变小鼠前脑中的转录组学改变和潜在的分子机制，并深入探索改变的表观遗传信息的细胞自主效应。此外，我们观察到细胞非自主发育缺陷的interneuron谱系内的DOT 1 L的损失amatergic谱系。我们建议将scRNA和scATAC数据扩展到进一步的发育时间点，并深入分析源自神经元的信号通路，这些信号通路影响发育中皮质板的中间神经元数量。总之，这个项目将启发一个表观遗传机制，有助于平衡大脑皮层中的谷氨酸能和GABA能神经元的数量。了解这一基本的发展原则是非常重要的，以评估表观遗传学是否是一种手段，以预防或治疗，例如与受损的兴奋性/抑制性信息处理相关的精神疾病。