title: LHX2 Interacts with the NuRD Complex and Regulates Cortical Neuron Subtype Determinants Fezf2 and Sox11.
abstract: In the developing cerebral cortex, sequential transcriptional programs take neuroepithelial cells from proliferating progenitors to differentiated neurons with unique molecular identities. The regulatory changes that occur in the chromatin of the progenitors are not well understood. During deep layer neurogenesis, we show that transcription factor LHX2 binds to distal regulatory elements of Fezf2 and Sox11, critical determinants of neuron subtype identity in the mouse neocortex. We demonstrate that LHX2 binds to the nucleosome remodeling and histone deacetylase histone remodeling complex subunits LSD1, HDAC2, and RBBP4, which are proximal regulators of the epigenetic state of chromatin. When LHX2 is absent, active histone marks at the Fezf2 and Sox11 loci are increased. Loss of LHX2 produces an increase, and overexpression of LHX2 causes a decrease, in layer 5 Fezf2 and CTIP2-expressing neurons. Our results provide mechanistic insight into how LHX2 acts as a necessary and sufficient regulator of genes that control cortical neuronal subtype identity.
  
  
  
  The functional complexity of the cerebral cortex arises from an array of distinct neuronal subtypes with unique connectivity patterns that are produced from common progenitors. This study reveals that transcription factor LHX2 regulates the numbers of specific cortical output neuron subtypes by controlling the genes that are required to produce them. Loss or increase in LHX2 during neurogenesis is sufficient to increase or decrease, respectively, a particular subcerebrally projecting population. Mechanistically, LHX2 interacts with chromatin modifying protein complexes to edit the chromatin landscape of its targets Fezf2 and Sox11, which regulates their expression and consequently the identities of the neurons produced. Thus, LHX2 is a key component of the control network for producing neurons that will participate in cortical circuitry.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Bhavana
authors.identifier: 0000-0003-1184-0833
authors.initials: B
authors.lastname: Muralidharan
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Zeba
authors.initials: Z
authors.lastname: Khatri
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Upasana
authors.initials: U
authors.lastname: Maheshwari
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Ritika
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Basabdatta
authors.initials: B
authors.lastname: Roy
authors.affiliation: Indian Institute of Science, Education, and Research, Pune 411008, India.|Symbiosis School of Biomedical Sciences, Symbiosis International University, Lavale, Pune.
authors.forename: Saurabh J
authors.initials: SJ
authors.lastname: Pradhan
authors.affiliation: Indian Institute of Science, Education, and Research, Pune 411008, India.
authors.forename: Krishanpal
authors.initials: K
authors.lastname: Karmodiya
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.|Department of Stem Cell and Regenerative Biology and.|Center for Brain Science, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138.
authors.forename: Hari
authors.identifier: 0000-0002-2289-0249
authors.initials: H
authors.lastname: Padmanabhan
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.|Department of Stem Cell and Regenerative Biology and.
authors.forename: Ashwin S
authors.identifier: 0000-0002-2812-7674
authors.initials: AS
authors.lastname: Shetty
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Chinthapalli
authors.initials: C
authors.lastname: Balaji
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Ullas
authors.identifier: 0000-0003-2612-1743
authors.initials: U
authors.lastname: Kolthur-Seetharam
authors.affiliation: Department of Stem Cell and Regenerative Biology and.|Center for Brain Science, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138.
authors.forename: Jeffrey D
authors.identifier: 0000-0003-3662-9698
authors.initials: JD
authors.lastname: Macklis
authors.affiliation: Indian Institute of Science, Education, and Research, Pune 411008, India.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Galande
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India, shubhatole@gmail.com.
authors.forename: Shubha
authors.identifier: 0000-0001-6584-443X
authors.initials: S
authors.lastname: Tole
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology* / Q000000981:diagnostic imaging; D002843:Chromatin / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008297:Male; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D009707:Nucleosomes / Q000378:metabolism; D011247:Pregnancy; D055751:SOXC Transcription Factors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D060850:LIM-Homeodomain Proteins; C489784:Lhx2 protein, mouse; D009419:Nerve Tissue Proteins; D009707:Nucleosomes; D055751:SOXC Transcription Factors; C490793:Sox11 protein, mouse; D014157:Transcription Factors; C412364:Zfp312 protein, mouse; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
keywords: cell fate; chromatin; epigenetics; lamination; progenitor; specification