title: Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development.
abstract: Jarid2 is part of the Polycomb Repressor complex 2 (PRC2) responsible for genome-wide H3K27me3 deposition. Unlike other PRC2-deficient embryonic stem cells (ESCs), however, Jarid2-deficient ESCs show a severe differentiation block, altered colony morphology, and distinctive patterns of deregulated gene expression. Here, we show that Jarid2(-/-) ESCs express constitutively high levels of Nanog but reduced PCP signaling components Wnt9a, Prickle1, and Fzd2 and lowered β-catenin activity. Depletion of Wnt9a/Prickle1/Fzd2 from wild-type ESCs or overexpression of Nanog largely phenocopies these cellular defects. Co-culture of Jarid2(-/-) with wild-type ESCs restores variable Nanog expression and β-catenin activity and can partially rescue the differentiation block of mutant cells. In addition, we show that ESCs lacking Jarid2 or Wnt9a/Prickle1/Fzd2 or overexpressing Nanog induce multiple ICM formation when injected into normal E3.5 blastocysts. These data describe a previously unrecognized role for Jarid2 in regulating a core pluripotency and Wnt/PCP signaling circuit that is important for ESC differentiation and for pre-implantation development.
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK; Department of Computer Science and A. I., University of Granada, Centre for Genomics and Oncological Research (GENYO), Avenue de la Ilustracion 114, 18016 Granada, Spain. Electronic address: davidlandeira@ugr.es.
authors.forename: David
authors.initials: D
authors.lastname: Landeira
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Hakan
authors.initials: H
authors.lastname: Bagci
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Andrzej R
authors.initials: AR
authors.lastname: Malinowski
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Brown
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Soza-Ried
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Amelie
authors.initials: A
authors.lastname: Feytout
authors.affiliation: Transgenics and Embryonic Stem Cell Laboratory, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Webster
authors.affiliation: Transgenics and Embryonic Stem Cell Laboratory, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Elodie
authors.initials: E
authors.lastname: Ndjetehe
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Cantone
authors.affiliation: Department of Computer Science and A. I., University of Granada, Centre for Genomics and Oncological Research (GENYO), Avenue de la Ilustracion 114, 18016 Granada, Spain.
authors.forename: Helena G
authors.initials: HG
authors.lastname: Asenjo
authors.affiliation: Developmental Epigenetics Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford 1 3QU, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Brockdorff
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Electronic address: amanda.fisher@csc.mrc.ac.uk.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001755:Blastocyst / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051157:Frizzled Receptors; C489743:Fzd2 protein, mouse; D018398:Homeodomain Proteins; C093650:Jarid2 protein, mouse; D060588:LIM Domain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; C524253:Prickle1 protein, mouse; D051153:Wnt Proteins; C486388:Wnt9a protein, mouse; D051176:beta Catenin; D063151:Polycomb Repressive Complex 2