title: Active repression by RARγ signaling is required for vertebrate axial elongation.
abstract: Retinoic acid receptor gamma 2 (RARγ2) is the major RAR isoform expressed throughout the caudal axial progenitor domain in vertebrates. During a microarray screen to identify RAR targets, we identified a subset of genes that pattern caudal structures or promote axial elongation and are upregulated by increased RAR-mediated repression. Previous studies have suggested that RAR is present in the caudal domain, but is quiescent until its activation in late stage embryos terminates axial elongation. By contrast, we show here that RARγ2 is engaged in all stages of axial elongation, not solely as a terminator of axial growth. In the absence of RA, RARγ2 represses transcriptional activity in vivo and maintains the pool of caudal progenitor cells and presomitic mesoderm. In the presence of RA, RARγ2 serves as an activator, facilitating somite differentiation. Treatment with an RARγ-selective inverse agonist (NRX205099) or overexpression of dominant-negative RARγ increases the expression of posterior Hox genes and that of marker genes for presomitic mesoderm and the chordoneural hinge. Conversely, when RAR-mediated repression is reduced by overexpressing a dominant-negative co-repressor (c-SMRT), a constitutively active RAR (VP16-RARγ2), or by treatment with an RARγ-selective agonist (NRX204647), expression of caudal genes is diminished and extension of the body axis is prematurely terminated. Hence, gene repression mediated by the unliganded RARγ2-co-repressor complex constitutes a novel mechanism to regulate and facilitate the correct expression levels and spatial restriction of key genes that maintain the caudal progenitor pool during axial elongation in Xenopus embryos.
authors.affiliation: Department of Developmental and Cell Biology, 2011 Biological Sciences 3, University of California, Irvine, CA 92697-2300, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Janesick
authors.affiliation: Department of Developmental and Cell Biology, 2011 Biological Sciences 3, University of California, Irvine, CA 92697-2300, USA.
authors.forename: Tuyen T L
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Aisaki
authors.affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitajima
authors.affiliation: IO Therapeutics, Santa Ana, CA 92705-5851, USA.
authors.forename: Roshantha A S
authors.initials: RA
authors.lastname: Chandraratna
authors.affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.affiliation: Department of Developmental and Cell Biology, 2011 Biological Sciences 3, University of California, Irvine, CA 92697-2300, USA Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697-2300, USA blumberg@uci.edu.
authors.forename: Bruce
authors.initials: B
authors.lastname: Blumberg
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000235:genetics; D056970:Co-Repressor Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000502:physiology; D009420:Nervous System / Q000196:embryology / Q000254:growth & development; D009474:Neurons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D019170:Somites / Q000502:physiology; D013997:Time Factors; D029867:Xenopus Proteins / Q000378:metabolism; D014982:Xenopus laevis; D000097768:Retinoic Acid Receptor gamma
chemical_list: D056970:Co-Repressor Proteins; D018398:Homeodomain Proteins; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D029867:Xenopus Proteins; D000097768:Retinoic Acid Receptor gamma; C490471:NCOR2 protein, Xenopus; C000607071:RARA protein, human; C082925:retinoic acid receptor beta
keywords: Active repression; Axial elongation; Chordoneural hinge; Posterior Hox; Presomitic mesoderm; Retinoic acid receptor