title: Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons.
abstract: The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors and chromatin are thought to regulate gene expression. In the medial ganglionic eminence, the NKX2-1 transcription factor controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. Here, we dissected the molecular functions of NKX2-1 by defining its chromosomal binding, regulation of gene expression, and epigenetic state. NKX2-1 binding at distal regulatory elements 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.
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Magnus
authors.initials: M
authors.lastname: Sandberg
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Flandin
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Shanni
authors.initials: S
authors.lastname: Silberberg
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95817, USA; Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Su-Feher
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Price
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jia Sheng
authors.initials: JS
authors.lastname: Hu
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Kim
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; School of Natural Sciences, University of California, Merced, CA 95343, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95817, USA; Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, CA 95616, USA. Electronic address: asnord@davis.edu.
authors.forename: Alex S
authors.initials: AS
authors.lastname: Nord
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: john.rubenstein@ucsf.edu.
authors.forename: John L R
authors.initials: JLR
authors.lastname: Rubenstein
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000166:cytology* / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D024721:E-Box Elements / Q000235:genetics; D063185:Epigenetic Repression / Q000235:genetics; D059330:GABAergic Neurons / Q000166:cytology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002843:Chromatin; C490147:Gbx1 protein, mouse; C513182:Gbx2 protein, mouse; D018398:Homeodomain Proteins; C498504:LHX6 protein, mouse; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors