Telencephalic GABAergic neurons have central roles in cognition, movement and emotion. Dysfunction of these neurons is implicated in epilepsy, intellectual deficiency, autism and schizophrenia. During development, medial ganglionic eminence (MGE) progenitors generate a diversity of GABAergic neurons including Somatostatin (SST+) and Parvalbumin (PV+) cortical interneurons (CINs), and basal ganglia projection neurons. The identities of MGE-derived neurons are determined by the location within the MGE progenitor domain where they are specified, and the time during development when they are produced. Understanding the transcriptional networks that govern spatial and temporal specification is crucial for determining the basic mechanisms of telencephalic GABAergic development, and how dysfunction of these networks can contribute to neuropsychiatric disorders. To elucidate the transcriptional networks driving the development of MGE progenitors and their derivatives, we must define the transcription factors (TFs) and regulatory elements (REs) involved, as well as the coding regions that they control. We hypothesize that spatially and temporally specific transcriptional circuits control telencephalic GABAergic neuron diversity. We propose a combination of genetic and genomic experiments in mice aimed at elucidating the networks of TFs that regulate the development of neurons generated in the MGE. Our approach leverages genetic labeling to selectively purify and manipulate specific MGE lineages, which will allow us to integrate transcriptomic and epigenomic data. We will define RNA expression in different MGE regions and at different ages using novel temporally-inducible CreER lines whose activities are regionally specific (Aim 1). We will then use Histone ChIP-Seq and ATAC-Seq to identify genomic regions (candidate REs) that have spatially and temporally dynamic epigenomic states; we will also use TF ChIP-Seq to identify in vivo binding sites for COUPTF1/2 and MAF/MAFB (Aim 2). From these data, we will begin to uncover the transcriptional circuits controlling MGE specification. The circuit models will be tested using mouse mutants that lack COUPTF1/2 and MAF/MAFB, TFs that we hypothesize regulate GABAergic neuron diversity in a temporal- and spatial- dependent manner (Aim 3 & 4). Elucidating transcription circuits driving telencephalic GABAergic development provides a fundamental framework for understanding the genetic pathways, including the REs, that generate GABAergic neuron diversity and that may be dysregulated in neuropsychiatric disorders.
Disruption of cerebral cortex and basal ganglia development and function are strongly associated with several major neuropsychiatric disorders, including intellectual deficiency, epilepsy, cerebral palsy, autism and schizophrenia. The experiments proposed in this application aim to elucidate basic mechanisms that underlie normal development of GABAergic neurons of basal ganglia and cerebral cortex. This information will provide a key foundation for understanding the genetic and molecular mechanisms underlying many neuropsychiatric disorders.
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