title: A direct fate exclusion mechanism by Sonic hedgehog-regulated transcriptional repressors.
abstract: Sonic hedgehog (Shh) signaling patterns the vertebrate spinal cord by activating a group of transcriptional repressors in distinct neural progenitors of somatic motor neuron and interneuron subtypes. To identify the action of this network, we performed a genome-wide analysis of the regulatory actions of three key ventral determinants in mammalian neural tube patterning: Nkx2.2, Nkx6.1 and Olig2. Previous studies have demonstrated that each factor acts predominantly as a transcriptional repressor, at least in part, to inhibit alternative progenitor fate choices. Here, we reveal broad and direct repression of multiple alternative fates as a general mechanism of repressor action. Additionally, the repressor network targets multiple Shh signaling components providing negative feedback to ongoing Shh signaling. Analysis of chromatin organization around Nkx2.2-, Nkx6.1- and Olig2-bound regions, together with co-analysis of engagement of the transcriptional activator Sox2, indicate that repressors bind to, and probably modulate the action of, neural enhancers. Together, the data suggest a model for neural progenitor specification downstream of Shh signaling, in which Nkx2.2 and Olig2 direct repression of alternative neural progenitor fate determinants, an action augmented by the overlapping activity of Nkx6.1 in each cell type. Integration of repressor and activator inputs, notably activator inputs mediated by Sox2, is probably a key mechanism in achieving cell type-specific transcriptional outcomes in mammalian neural progenitor fate specification.
authors: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.
authors: Yuichi
authors: Y
authors: Nishi
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors: Xiaoxiao
authors: X
authors: Zhang
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Jieun
authors: J
authors: Jeong
authors: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.
authors: Kevin A
authors: KA
authors: Peterson
authors: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors: Anastasia
authors: A
authors: Vedenko
authors: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors: Martha L
authors: ML
authors: Bulyk
authors: Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors: Winston A
authors: WA
authors: Hide
authors: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA amcmahon@med.usc.edu.
authors: Andrew P
authors: AP
authors: McMahon
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002843:Chromatin / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000166:cytology; D008954:Models, Biological; D009046:Motor Neurons / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology*; D054259:Neural Tube / Q000196:embryology* / Q000378:metabolism; D009687:Nuclear Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D016366:Open Reading Frames / Q000235:genetics; D040081:Protein Array Analysis; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D029961:Zebrafish Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D053823:Hedgehog Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715631:NKX2-2 protein, human; C105201:NKX6-1 protein, human; C000715627:Nkx2-2 protein, mouse; C405708:OLIG2 protein, human; C527782:SOX2 protein, human; C000715630:nkx2.2b protein, zebrafish
keywords: Fate specification; Mouse; Neural development; Transcriptional regulation