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Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons

ABSTRACT: Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons

PROVIDER: PRJNA339133 | ENA |

REPOSITORIES: ENA

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Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons (microarray)

Project description:The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors (TFs), regulatory elements (REs), and chromatin are thought to precisely regulate gene expression. In the medial ganglionic eminence (MGE), the NKX2-1 TF controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. We dissected the molecular functions of NKX2-1 by defining its chromosomal binding regions, regulation of gene expression and epigenetic state. NKX2-1 binding at distal REs led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, Nkx2-1 is required to establish a permissive chromatin state and transcriptional activation in the sub- ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach provides a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants.

2016-09-21 | GSE85703 | GEO

Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons (ChIP-Seq)

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Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons.

Project description: Not available

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Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons

Project description:This SuperSeries is composed of the SubSeries listed below.

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Project description:Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons (microarray)

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Project description:Transplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches. Comparison of iGABA-INs transcriptional profile with those of starting fibroblasts and GAD67-GFP+ cortical interneurons.

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Genomic Resolution of DLX-orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons

Project description:DLX transcription factors (TFs) are master regulators of the developing vertebrate brain, driving forebrain GABAergic neuronal differentiation. Ablation of Dlx1&2 alters expression of genes that are critical for forebrain GABAergic development. We integrated epigenomic and transcriptomic analyses, complemented with in situ hybridization (ISH), and in vivo and in vitro studies of regulatory element (RE) function. This elucidated the DLX-organized gene regulatory network at genomic, cellular, and spatial level in mouse embryonic basal ganglia. DLX TFs perform dual activating and repressing functions; the consequences of their binding were determined by the sequence and genomic context of target loci. Our results reveal and, in part, explain the paradox of widespread DLX binding contrasted with a limited subset of target loci that are sensitive at the epigenomic and transcriptomic level to Dlx1&2 ablation. The regulatory properties identified here for DLX TFs suggest general mechanisms by which TFs orchestrate dynamic expression programs underlying neurodevelopment.

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Genomic Resolution of DLX-orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons

Project description:Genomic Resolution of DLX-orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons

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