Pbx Regulates Patterning of the Cerebral Cortex in Progenitors and Postmitotic Neurons

We demonstrate using conditional mutagenesis that Pbx1, with and without Pbx2(+/-) sensitization, regulates regional identity and laminar patterning of the developing mouse neocortex in cortical progenitors (Emx1-Cre) and in newly generated neurons (Nex1-Cre). Pbx1/2 mutants have three salient molecular phenotypes of cortical regional and laminar organization: hypoplasia of the frontal cortex, ventral expansion of the dorsomedial cortex, and ventral expansion of Reelin expression in the cortical plate of the frontal cortex, concomitant with an inversion of cortical layering in the rostral cortex. Molecular analyses, including PBX ChIP-seq, provide evidence that PBX promotes frontal cortex identity by repressing genes that promote dorsocaudal fate.

[1]  J. Berthelsen,et al.  Prep1, a novel functional partner of Pbx proteins , 1998, The EMBO journal.

[2]  D. Kaplan,et al.  FoxP2 Regulates Neurogenesis during Embryonic Cortical Development , 2013, The Journal of Neuroscience.

[3]  O. Hermanson,et al.  Genetic targeting of principal neurons in neocortex and hippocampus of NEX‐Cre mice , 2006, Genesis.

[4]  T. Abe,et al.  The Mammalian DM Domain Transcription Factor Dmrta2 Is Required for Early Embryonic Development of the Cerebral Cortex , 2012, PloS one.

[5]  J. Piven,et al.  An MRI study of brain size in autism. , 1995, The American journal of psychiatry.

[6]  Rebecca D Hodge,et al.  Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex , 2010, Proceedings of the National Academy of Sciences.

[7]  J. Rubenstein,et al.  CXCR4 and CXCR7 Have Distinct Functions in Regulating Interneuron Migration , 2011, Neuron.

[8]  P. Gruss,et al.  Pax6 Modulates the Dorsoventral Patterning of the Mammalian Telencephalon , 2000, The Journal of Neuroscience.

[9]  J. Berthelsen,et al.  The novel homeoprotein Prep1 modulates Pbx–Hox protein cooperativity , 1998, The EMBO journal.

[10]  T. Jessell,et al.  Control of Interneuron Fate in the Developing Spinal Cord by the Progenitor Homeodomain Protein Dbx1 , 2001, Neuron.

[11]  J. van Helden,et al.  RSAT peak-motifs: motif analysis in full-size ChIP-seq datasets , 2011, Nucleic acids research.

[12]  J. Rubenstein,et al.  Sp8 and COUP-TF1 reciprocally regulate patterning and Fgf signaling in cortical progenitors. , 2014, Cerebral cortex.

[13]  I. Weissman,et al.  The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. , 2001, Blood.

[14]  A. McMahon,et al.  A local Wnt-3a signal is required for development of the mammalian hippocampus. , 2000, Development.

[15]  O. Paulsen,et al.  Novel markers reveal subpopulations of subplate neurons in the murine cerebral cortex. , 2009, Cerebral cortex.

[16]  Karla E. Hirokawa,et al.  Lhx2 Selector Activity Specifies Cortical Identity and Suppresses Hippocampal Organizer Fate , 2008, Science.

[17]  S. Antonarakis,et al.  Meis1 and pKnox1 bind DNA cooperatively with Pbx1 utilizing an interaction surface disrupted in oncoprotein E2a-Pbx1. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  N. Andreasen,et al.  Insular cortex abnormalities in schizophrenia: a structural magnetic resonance imaging study of first-episode patients , 2000, Schizophrenia Research.

[19]  Hidetoshi Shimodaira,et al.  Pvclust: an R package for assessing the uncertainty in hierarchical clustering , 2006, Bioinform..

[20]  M. Greenberg,et al.  Neurogenin Promotes Neurogenesis and Inhibits Glial Differentiation by Independent Mechanisms , 2001, Cell.

[21]  D. O'Leary,et al.  Lhx2 specifies regional fate in Emx1 lineage of telencephalic progenitors generating cerebral cortex , 2009, Nature Neuroscience.

[22]  T R Bürglin,et al.  Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. , 1997, Nucleic acids research.

[23]  T. Capellini,et al.  Pbx homeodomain proteins: TALEnted regulators of limb patterning and outgrowth , 2011, Developmental dynamics : an official publication of the American Association of Anatomists.

[24]  Hani Z. Girgis,et al.  A High-Resolution Enhancer Atlas of the Developing Telencephalon , 2013, Cell.

[25]  J. Rubenstein,et al.  Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants , 2003, Development.

[26]  S. Chanda,et al.  Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. , 2001, Development.

[27]  C. Walsh,et al.  Expression of Cux‐1 and Cux‐2 in the subventricular zone and upper layers II–IV of the cerebral cortex , 2004, The Journal of comparative neurology.

[28]  B. Molyneaux,et al.  Bhlhb5 Regulates the Postmitotic Acquisition of Area Identities in Layers II-V of the Developing Neocortex , 2008, Neuron.

[29]  A. Visel,et al.  ChIP-seq accurately predicts tissue-specific activity of enhancers , 2009, Nature.

[30]  D. Amaral,et al.  Neuroanatomy of autism , 2008, Trends in Neurosciences.

[31]  E. Grove,et al.  The cortical hem regulates the size and patterning of neocortex , 2014, Development.

[32]  D. Zinyk,et al.  Basic Helix-Loop-Helix Transcription Factors Cooperate To Specify a Cortical Projection Neuron Identity , 2007, Molecular and Cellular Biology.

[33]  D. O'Leary,et al.  Regulation of area identity in the mammalian neocortex by Emx2 and Pax6. , 2000, Science.

[34]  T. Obayashi,et al.  Dmrta1 regulates proneural gene expression downstream of Pax6 in the mammalian telencephalon , 2013, Genes to cells : devoted to molecular & cellular mechanisms.

[35]  S. Mcconnell,et al.  Mutations in the BMP pathway in mice support the existence of two molecular classes of holoprosencephaly , 2007, Development.

[36]  L. Mishra,et al.  TGF-β Signaling in Development , 2007, Science's STKE.

[37]  V. Lefebvre,et al.  SOX5 postmitotically regulates migration, postmigratory differentiation, and projections of subplate and deep-layer neocortical neurons , 2008, Proceedings of the National Academy of Sciences.

[38]  Luca Muzio,et al.  Emx1, emx2 and pax6 in specification, regionalization and arealization of the cerebral cortex. , 2003, Cerebral cortex.

[39]  Cory Y. McLean,et al.  GREAT improves functional interpretation of cis-regulatory regions , 2010, Nature Biotechnology.

[40]  D. Wotton,et al.  Cooperative Transcriptional Activation by Klf4, Meis2, and Pbx1 , 2011, Molecular and Cellular Biology.

[41]  Y. Hirayasu,et al.  Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study , 2004, Psychiatry Research: Neuroimaging.

[42]  Joel I. Pritchard,et al.  NeuroD2 is necessary for development and survival of central nervous system neurons. , 2001, Developmental biology.

[43]  Shen-Ju Chou,et al.  COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas , 2007, Nature Neuroscience.

[44]  F. Guillemot,et al.  A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. , 2000, Genes & development.

[45]  Luis Puelles,et al.  Cortical Excitatory Neurons and Glia, But Not GABAergic Neurons, Are Produced in the Emx1-Expressing Lineage , 2002, The Journal of Neuroscience.

[46]  Anastassia Stoykova,et al.  Gene networks controlling early cerebral cortex arealization , 2006, The European journal of neuroscience.

[47]  L. Selleri,et al.  Hox and Pbx factors control retinoic acid synthesis during hindbrain segmentation. , 2011, Developmental cell.

[48]  S. Rose,et al.  An Endocrine-Exocrine Switch in the Activity of the Pancreatic Homeodomain Protein PDX1 through Formation of a Trimeric Complex with PBX1b and MRG1 (MEIS2) , 1998, Molecular and Cellular Biology.

[49]  M. Rocchi,et al.  PKNOX1, a gene encoding PREP1, a new regulator of Pbx activity, maps on human chromosome 21q22.3 and murine chromosome 17B/C. , 1998, Genomics.

[50]  Fumiko Itoh,et al.  Signaling of transforming growth factor‐β family members through Smad proteins , 2000 .

[51]  P. Arlotta,et al.  SOX5 Controls the Sequential Generation of Distinct Corticofugal Neuron Subtypes , 2008, Neuron.

[52]  D. O'Leary,et al.  Geniculocortical Input Drives Genetic Distinctions Between Primary and Higher-Order Visual Areas , 2013, Science.

[53]  J. D. Macklis,et al.  Lmo4 Establishes Rostral Motor Cortex Projection Neuron Subtype Diversity , 2013, The Journal of Neuroscience.

[54]  J. Kapfhammer,et al.  The ExDression Pattern of the Orphan Nuclear Receptor RORβ in the Developing and Adult Rat Nervous System Suggests a Role in the Processing of Sensory Information and in Circadian Rhythm , 1997, The European journal of neuroscience.

[55]  J. Olie,et al.  L’hypothèse neurodéveloppementale dans la schizophrénie , 2004 .

[56]  T. Capellini,et al.  Pbx1/Pbx2 govern axial skeletal development by controlling Polycomb and Hox in mesoderm and Pax1/Pax9 in sclerotome. , 2008, Developmental biology.

[57]  H. Hamada,et al.  Interplay of SOX and POU Factors in Regulation of the Nestin Gene in Neural Primordial Cells , 2004, Molecular and Cellular Biology.

[58]  Stefan Krauss,et al.  COUP-TFI coordinates cortical patterning, neurogenesis, and laminar fate and modulates MAPK/ERK, AKT, and beta-catenin signaling. , 2008, Cerebral cortex.

[59]  M. Seike,et al.  The reeler gene-associated antigen on cajal-retzius neurons is a crucial molecule for laminar organization of cortical neurons , 1995, Neuron.

[60]  J. D. Macklis,et al.  Molecular logic of neocortical projection neuron specification, development and diversity , 2013, Nature Reviews Neuroscience.

[61]  M. Goumans,et al.  Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. , 2000, The International journal of developmental biology.

[62]  D. Srivastava,et al.  Pbx1/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and Shh expression , 2006, Development.

[63]  J. Rubenstein,et al.  Patterning of frontal cortex subdivisions by Fgf17 , 2007, Proceedings of the National Academy of Sciences.

[64]  Juan Carlos Izpisua Belmonte,et al.  Sp8 exhibits reciprocal induction with Fgf8 but has an opposing effect on anterior-posterior cortical area patterning , 2007, Neural Development.

[65]  A. Castro,et al.  Partial inhibition of Cdk1 in G2 phase overrides the SAC and decouples mitotic events , 2014, Cell cycle.

[66]  D. O'Leary,et al.  Postmitotic regulation of sensory area patterning in the mammalian neocortex by Lhx2 , 2015, Proceedings of the National Academy of Sciences.

[67]  J. Moskow,et al.  AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins , 1997, Molecular and cellular biology.

[68]  R. Hevner,et al.  Postmitotic control of sensory area specification during neocortical development , 2014, Nature Communications.

[69]  J. Rubenstein,et al.  Frontal cortex subdivision patterning is coordinately regulated by Fgf8, Fgf17, and Emx2 , 2008, The Journal of comparative neurology.

[70]  C. Walsh,et al.  Patterning of the Dorsal Telencephalon and Cerebral Cortex by a Roof Plate-Lhx2 Pathway , 2001, Neuron.

[71]  H. Adesnik,et al.  Regional Distribution of Cortical Interneurons and Development of Inhibitory Tone Are Regulated by Cxcl12/Cxcr4 Signaling , 2008, The Journal of Neuroscience.

[72]  E. Grove,et al.  Neocortex Patterning by the Secreted Signaling Molecule FGF8 , 2001, Science.

[73]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[74]  M. Goumans,et al.  Signaling of transforming growth factor-beta family members through Smad proteins. , 2000, European journal of biochemistry.

[75]  Tadashi Hamasaki,et al.  EMX2 Regulates Sizes and Positioning of the Primary Sensory and Motor Areas in Neocortex by Direct Specification of Cortical Progenitors , 2004, Neuron.

[76]  G. Bejerano,et al.  Control of pelvic girdle development by genes of the Pbx family and Emx2 , 2011, Developmental dynamics : an official publication of the American Association of Anatomists.

[77]  J. Rubenstein,et al.  Neuronal production and precursor proliferation defects in the neocortex of mice with loss of function in the canonical Wnt signaling pathway , 2006, Neuroscience.

[78]  J. Casanova,et al.  Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. , 2012, Developmental cell.

[79]  S. Mcconnell,et al.  The determination of projection neuron identity in the developing cerebral cortex , 2008, Current Opinion in Neurobiology.

[80]  D. O'Leary,et al.  Graded and Areal Expression Patterns of Regulatory Genes and Cadherins in Embryonic Neocortex Independent of Thalamocortical Input , 1999, The Journal of Neuroscience.

[81]  J. Rubenstein,et al.  Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. , 2001, Development.

[82]  I. Rambaldi,et al.  Cooperative interactions between HOX and PBX proteins mediated by a conserved peptide motif , 1995, Molecular and cellular biology.

[83]  Luca Muzio,et al.  Area identity shifts in the early cerebral cortex of Emx2−/− mutant mice , 2000, Nature Neuroscience.

[84]  J. Rubenstein,et al.  Early neocortical regionalization in the absence of thalamic innervation. , 1999, Science.

[85]  R. Hevner,et al.  The protomap is propagated to cortical plate neurons through an Eomes-dependent intermediate map , 2013, Proceedings of the National Academy of Sciences.

[86]  J Galceran,et al.  Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1. , 2000, Development.

[87]  P. Arlotta,et al.  Neuronal subtype specification in the cerebral cortex , 2007, Nature Reviews Neuroscience.

[88]  Matthew J. Anderson,et al.  A conserved Pbx-Wnt-p63-Irf6 regulatory module controls face morphogenesis by promoting epithelial apoptosis. , 2011, Developmental cell.

[89]  H. Monyer,et al.  Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour , 2014, Molecular Psychiatry.

[90]  G. Sauvageau,et al.  Hox homeodomain proteins exhibit selective complex stabilities with Pbx and DNA. , 1996, Nucleic acids research.

[91]  E. Grove,et al.  LIM-homeodomain gene Lhx2 regulates the formation of the cortical hem , 2001, Mechanisms of Development.

[92]  Winnie S. Liang,et al.  Dlx1&2 and Mash1 transcription factors control striatal patterning and differentiation through parallel and overlapping pathways , 2009, The Journal of comparative neurology.

[93]  N. Franck,et al.  [Neurodevelopmental hypothesis of schizophrenia]. , 2002, La Revue du praticien.

[94]  F. Luyten,et al.  Xenopus SMOC-1 Inhibits Bone Morphogenetic Protein Signaling Downstream of Receptor Binding and Is Essential for Postgastrulation Development in Xenopus , 2009, The Journal of Biological Chemistry.

[95]  Kevin S. Smith,et al.  The TALE Homeodomain Protein Pbx2 Is Not Essential for Development and Long-Term Survival , 2004, Molecular and Cellular Biology.

[96]  Mark J. Murphy,et al.  Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence. , 2008, Cell stem cell.