Telencephalic GABAergic neurons in the basal ganglia and cerebral cortex have central roles in cognition and emotion. Dysfunction of these neurons contributes to some types of epilepsy, intellectual deficiency, autism and schizophrenia. During development, subpallial progenitors generate most of telencephalic GABAergic neurons, including basal ganglia projections neurons and cortical interneurons6. The Dlx1,2,5&6 homeodomain transcription factors (TF) have central roles for this process7-24. Understanding the genetic circuitry upstream and downstream of the DLX TFs is essential for elucidating the basic mechanisms of telencephalic GABAergic development. To elucidate the genetic circuitry driving the development and function of telencephalic GABAergic progenitors and neurons, we must define the TFs, REs (enhancers and promoters) and the coding regions that they control. We hypothesize that the DLX homeodomain (TF) are at the core of transcriptional circuits, which we call the ?Dlx Pathway?, that regulate the development of most telencephalic GABAergic neurons, including basal ganglia projections neurons and cortical interneurons. We propose experiments aimed at elucidating the network of TFs in the Dlx Pathway that directly regulate genes controlling development of cells generated in the embryonic basal ganglia (ganglionic eminences, GEs). We will use chromatin immunoprecipitation followed by whole genome sequencing (ChIP-Seq) to elucidate in vivo genomic binding sites for TFs upstream and downstream of Dlx1&2 (Aim 1). Analysis of changes in RNA expression in the GEs of Dlx1/2 mutants (Aim 2) will provide evidence for the genes whose expression depends on Dlx function. Histone ChIP-Seq and ATAC- Seq (Aim 3), in conjunction with TF ChIP-Seq, will provide evidence for the locations of regulatory elements (REs; enhancers and promoters) used by Dlx Pathway. Final we will assay RE activity using transgenic methods (Aims 4&5). Elucidating transcription circuits driving telencephalic GABAergic development provides a fundamental framework for understanding the genetic pathways, including the REs, which generate inhibitory neurons. !
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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