Int. J. Biol. Sci. 2006, 2 38International Journal of Biological Sciences ISSN 1449-2288 www.biolsci.org 2006 2(2):38-47 ©2006 Ivyspring International Publisher. All rights reserved Review Retinoic acid signaling and the evolution of chordates Ferdinand Marlétaz1, Linda Z. Holland2, Vincent Laudet1 and Michael Schubert1 1. Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR5161/INRA 1237/ENS Lyon, IFR128 BioSciences/Lyon-Gerland, Ecole Normale Supérieure de Lyon, 46 Allée d’Italie, 69364 Lyon Cedex 07, France 2. Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093-0202, USA Corresponding address: V. Laudet, Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR5161/INRA 1237/ENS Lyon, IFR128 BioSciences/Lyon-Gerland, Ecole Normale Supérieure de Lyon, 46 Allée d’Italie, 69364 Lyon Cedex 07, France. E-mail: [email protected] - Tel: ++33 4 72 72 81 90 - Fax: ++33 4 72 72 80 80 Received: 2006.02.13; Accepted: 2006.03.15; Published: 2006.04.10 In chordates, which comprise urochordates, cephalochordates and vertebrates, the vitamin A-derived morphogen retinoic acid (RA) has a pivotal role during development. Altering levels of endogenous RA signaling during early embryology leads to severe malformations, mainly due to incorrect positional codes specifying the embryonic anteroposterior body axis. In this review, we present our current understanding of the RA signaling pathway and its roles during chordate development. In particular, we focus on the conserved roles of RA and its downstream mediators, the Hox genes, in conveying positional patterning information to different embryonic tissues, such as the endoderm and the central nervous system. We find that some of the control mechanisms governing RA-mediated patterning are well conserved between vertebrates and invertebrate chordates, such as the cephalochordate amphioxus. In contrast, outside the chordates, evidence for roles of RA signaling is scarce and the evolutionary origin of the RA pathway itself thus remains elusive. In sum, to fully understand the evolutionary history of the RA pathway, future research should focus on identification and study of components of the RA signaling cascade in non-chordate deuterostomes (such as hemichordates and echinoderms) and other invertebrates, such as insects, mollusks and cnidarians. Key words: amphioxus, anteroposterior patterning, Branchiostoma, deuterostomes, Hox, invertebrate-to-vertebrate transition, phylogeny 1. Introduction Among bilaterian animals, the deuterostomes include the hemichordates, the echinoderms and the chordates. The chordates can further be subdivided into urochordates (=tunicates), cephalochordates and vertebrates (Fig. 1A). Since human beings have often wondered about their own origins, it is not surprising that there have been many studies aimed at understanding the evolutionary history of chordates (i.e. the origin of chordates and the diversification of vertebrates). The main characters that evolved at the base of the chordates are a notochord and a dorsal hollow nerve cord [1], while definite neural crest cells and placodes arose at the base of the vertebrates [2]. However, the evolutionary origins of these structures have been controversial, mainly because of difficulties in determining homologies between chordate-specific characters and structures in non-chordate deuterostomes (i.e. in hemichordates and echinoderms) as well as between the vertebrate-specific characters and structures in invertebrate chordates. The development of many chordate- and vertebrate-specific characters is controlled, directly or indirectly, by retinoic acid (RA), a vitamin A-derived morphogen. In chordate embryos, too much or too little RA during early embryogenesis causes malformations, which are mainly due to a mispatterning of the embryo along the anteroposterior body axis. RA signaling is mediated by RA binding to retinoic acid receptors (RARs), which form heterodimers with retinoid X receptors (RXRs) [3]. During chordate development, important functions of RA signaling are mediated by Hox genes, at least some of which are direct targets of RA [4-6]. In many animals, including most deuterostomes, Hox genes mediate anteroposterior positional patterning of the embryo [7, 8]. Moreover, in vertebrates, Hox genes have been suggested to play important roles in the patterning of all embryonic tissue layers [7, 9]. Ever since it became clear that the genetic mechanisms controlling key features of embryonic development are highly conserved between organisms as diverse as fruit flies and mice, comparisons of the developmental mechanisms in different organisms have been used to address questions about animal evolution, particularly about the invertebrate-to-vertebrate transition in chordates [10]. Using this so-called “evo-devo” approach, this review discusses the developmental roles of RA signaling among chordates in regard to chordate origins and vertebrate evolution. The focus is on the roles of RA- and Hox-dependent patterning during development and their conservation during chordateInt. J. Biol. Sci. 2006, 2 39evolution. We show that some of the control mechanisms governing RA-mediated patterning are quite conserved among vertebrates and between vertebrates and invertebrate chordates, such as the cephalochordate amphioxus. In contrast, evidence for roles of RA signaling outside the chordates and the evolutionary origin of RA signaling itself still remain elusive. Figure 1. Deuterostome phylogeny and components of the RA signaling pathway in deuterostomes. A) Deuterostome phylogeny. Echinoderms and hemichordates together establish the sister group of chordates. The urochordates (=tunicates) include ascidians and appendicularians. Urochordates and cephalochordates are invertebrate chordates. The vertebrates include agnathan groups (hagfish and lampreys) as well as the gnathostome chondrichthyans (cartilaginous fish), actinopterygians (ray-finned fish) and sarcopterygians (lobe-finned fish and tetrapods). Within chordates, the phylogenetic relationships between cephalochordates and urochordates and between hagfish and lampreys are still disputed and their respective positions within the tree are thus shown as polytomies. Two important events during deuterostome evolution are the origin of chordates and the origin of vertebrates. The two rounds of extensive gene duplications early