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

皮层板由兴奋性神经元和抑制性神经元组成，后者起源于神经节突起。在胚胎发育过程中，中间神经元前体从它们的起源端脑腹侧迁移到皮层板的最终目的地。组蛋白甲基转移酶DOT1L是谷氨酸能神经元皮层板发育和层状分布所必需的，并以细胞自主和非自主的方式影响中间神经元的发育。内侧神经节嵴（MGE）衍生的中间神经元前体细胞中DOT1L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Parvalbumin （PVALB）表达的中间神经元。我们的研究结果表明，DOT1L缺失导致皮质中间神经元数量减少是有丝分裂后分化/成熟改变的结果。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RNA-和ATAC-seq更高的分辨率来充分认识DOT1L对皮质中间神经元的影响。我们建议使用scRNA-、scATAC-和scCUT&TAG来解析DOT1L突变小鼠前脑的转录组改变和潜在的分子机制，并深入探索表观遗传信息改变的细胞自主效应。此外，我们通过谷氨酸谱系中DOT1L的缺失观察到中间神经元谱系的细胞非自主发育缺陷。我们建议将scRNA和scatac数据扩展到进一步的发育时间点，并深入分析源自谷氨酸能神经元的信号通路，这些信号通路影响发育中的皮质板中中间神经元的数量。总之，该项目将启发一种表观遗传机制，有助于平衡大脑皮层中谷氨酸能和氨基丁酸能神经元的数量。理解这一基本的发育原理对于评估表观遗传学是否是预防或治疗精神疾病（例如与兴奋性/抑制性信息处理受损相关的精神疾病）的一种手段具有重要意义。

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.