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

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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.