Dissecting the epigenetic mechanisms of interneuron fate determination

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PROJECT SUMMARY/ABSTRACT The cerebral cortex contains enormous neuronal diversity that during development become integrated into a startling array of neural circuits. Despite comprising the minority of all neocortical cells, Inhibitory GABAergic interneurons (INs) play an important role in the stability of the circuits underlying cognitive and higher-order brain function. it is becoming evident that neuropsychiatric disorders disproportionately arise from insults affecting interneuron development, including epilepsy, autism, bipolar disorder, and schizophrenia. Therefore, characterizing the molecular mechanisms that control IN fate is crucial for our ability to understand the brain in health and disease. INs are born in the ventral telencephalon, primarily in the medial, caudal, and lateral ganglionic eminences (MGE, CGE, and LGE) and migrate tangentially to reach their settling position in the cortex. Despite their diversity, INs are classified into four non-overlapping functional cell types: parvalbumin (PV), somatostatin (SST), vasoactive-intestinal peptide (VIP), and Reelin-expressing cortical INs. However, little is known about the mechanisms of fate determination that control the establishment and diversification of these populations. Compounding the difficulty of studying these questions, INs are born embryonically but only acquire their subtype specific character in the second postnatal week. Genetic fate mapping and transplantation efforts indicate that embryonic progenitors preferentially give rise to defined populations in the adult brain. Yet transcriptional profiling of progenitors within the proliferative zones of the ganglionic eminences found homogenous programs with no clear evidence of fate bifurcation. Given that epigenetic regulation precedes the transcriptional output, this proposal seeks to better understand the mechanisms by which progenitors epigenetically commit to their mature fate (addressed in Aim 1). The proposed experiments will test the hypothesis that progenitors are epigenetically primed through active chromatin configurations at enhancer sites that precede the activation of cell-type specific transcriptional program. The focus of this proposal is on MGE progenitors that give rise to PV and SST cell types. Additionally, this proposal will examine how PV and SST cell identities are maintained during development by the epigenetic role of the Satb1 gene (addressed in Aim 2). To accomplish these aims, an integrative genomic analysis driven by an assay for transposase accessible chromatin (ATAC-seq) will be used to build an epigenomic map of regulatory regions that drive cell fate specification and maturation. This information will be used to elucidate the developmental trajectories of interneurons from progenitors to mature cell types. Ultimately, this information will improve our understanding of the spatial and temporal control of progenitor differentiation into distinct subclasses, which can be used to identify critical stages on interneuron development. This study will play an important role in identifying and treating neuropsychiatric diseases associated with cell-type specific interneuron dysfunction.