title: Evolution of retinoic acid receptors in chordates: insights from three lamprey species, Lampetra fluviatilis, Petromyzon marinus, and Lethenteron japonicum.
abstract: BACKGROUND
  Retinoic acid (RA) signaling controls many developmental processes in chordates, from early axis specification to late organogenesis. The functions of RA are chiefly mediated by a subfamily of nuclear hormone receptors, the retinoic acid receptors (RARs), that act as ligand-activated transcription factors. While RARs have been extensively studied in jawed vertebrates (that is, gnathostomes) and invertebrate chordates, very little is known about the repertoire and developmental roles of RARs in cyclostomes, which are extant jawless vertebrates. Here, we present the first extensive study of cyclostome RARs focusing on three different lamprey species: the European freshwater lamprey, Lampetra fluviatilis, the sea lamprey, Petromyzon marinus, and the Japanese lamprey, Lethenteron japonicum.
  
  
  RESULTS
  We identified four rar paralogs (rar1, rar2, rar3, and rar4) in each of the three lamprey species, and phylogenetic analyses indicate a complex evolutionary history of lamprey rar genes including the origin of rar1 and rar4 by lineage-specific duplication after the lamprey-hagfish split. We further assessed their expression patterns during embryonic development by in situ hybridization. The results show that lamprey rar genes are generally characterized by dynamic and highly specific expression domains in different embryonic tissues. In particular, lamprey rar genes exhibit combinatorial expression domains in the anterior central nervous system (CNS) and the pharyngeal region.
  
  
  CONCLUSIONS
  Our results indicate that the genome of lampreys encodes at least four rar genes and suggest that the lamprey rar complement arose from vertebrate-specific whole genome duplications followed by a lamprey-specific duplication event. Moreover, we describe a combinatorial code of lamprey rar expression in both anterior CNS and pharynx resulting from dynamic and highly specific expression patterns during embryonic development. This 'RAR code' might function in regionalization and patterning of these two tissues by differentially modulating the expression of downstream effector genes during development.
authors.affiliation: Molecular Zoology Team, Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, INRA, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France ; MRC Centre for Developmental Neurobiology, New Hunt's House, King's College London, Guy's Campus, London, SE1 1UL UK.
authors.forename: Florent
authors.initials: F
authors.lastname: Campo-Paysaa
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Colorado Boulder, Ramaley Biology, 1800 Colorado Avenue, Boulder, CO 80309 USA ; Department of Zoology, Comenius University in Bratislava, Mlynska Dolina B-1, 84215 Bratislava, Slovakia.
authors.forename: David
authors.initials: D
authors.lastname: Jandzik
authors.affiliation: Laboratory for Evolutionary Morphology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takio-Ogawa
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Colorado Boulder, Ramaley Biology, 1800 Colorado Avenue, Boulder, CO 80309 USA ; Department of Pediatrics, University of Colorado, Children's Hospital, 13065 East 17th Avenue, Aurora, CO 80045 USA.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Cattell
authors.affiliation: Department of Biology, Kalamazoo College, 1200 Academy Street, Kalamazoo, Michigan 49008 USA ; Division of Pediatric Gastroenterology, Department of Pediatrics and Communicable Diseases, University of Michigan, C.S. Mott Children's Hospital, 1540 East Hospital Drive SPC 4259, Ann Arbor, Michigan 48109 USA.
authors.forename: Haley C
authors.initials: HC
authors.lastname: Neef
authors.affiliation: Department of Biology, Kalamazoo College, 1200 Academy Street, Kalamazoo, Michigan 49008 USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Langeland
authors.affiliation: Laboratory for Evolutionary Morphology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kuratani
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Colorado Boulder, Ramaley Biology, 1800 Colorado Avenue, Boulder, CO 80309 USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Medeiros
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, FR2424, Station Biologique de Roscoff, Place Georges Teissier, 29680 Roscoff, France ; CNRS, FR2424, Station Biologique de Roscoff, Place Georges Teissier, 29680 Roscoff, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mazan
authors.affiliation: Genome Resource and Analysis Unit, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan ; Phyloinformatics Unit, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Kuraku
authors.affiliation: Molecular Zoology Team, Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, INRA, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudet
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, UMR 7009, Laboratoire de Biologie du Développement de Villefranche-sur-Mer, Observatoire Océanologique de Villefranche-sur-Mer, 181 Chemin du Lazaret, 06230 Villefranche-sur-Mer, France ; CNRS, UMR 7009, Laboratoire de Biologie du Développement de Villefranche-sur-Mer, Observatoire Océanologique de Villefranche-sur-Mer, 181 Chemin du Lazaret, 06230 Villefranche-sur-Mer, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Schubert
keywords: Agnathan; Cyclostome; Developmental patterning; Gene duplication; Gnathostome; RAR code; Retinoid signaling; Vertebrate