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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.
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 during vertebrate diversification are highlighted with green boxes labeled 'R'. B) Components of the RA pathway in deuterostomes. Deuterostome groups, for which a whole genome sequencing (WGS) project has already been finished are indicated with a turquoise â+â, those, for which a WGS project is underway, are marked with a turquoise â(+)â. If known, the exact number of RAR, Raldh and Cyp26 genes in the genome of a specific deuterostome group is indicated, the certain presence of a gene is marked with â+â and the lack of data is highlighted by â?â.
Figure 2. Synthesis, degradation and mode of action of retinoic acid (RA). A) The metabolic pathway for synthesis and degradation of endogenous RA is shown. RA is synthesized by oxidation of retinal by retinaldehyde dehydrogenases (RALDHs). In a reversible reaction, retinal is synthesized from retinol (vitamin A) by either aldehyde dehydrogenases (ADHs) or short-chain dehydrogenase/reductases (RDHs/SDRs). Cellular retinol binding proteins (CRBPs) can bind retinol, whereas cellular retinoic acid binding proteins (CRABPs) can bind RA. Finally, endogenous RA is degraded by CYP26 enzymes. B) The RAR/RXR heterodimer mediates the effects of RA. In the absence of ligand (RA), the RAR/RXR heterodimer is bound to DNA and co-repressors. This complex induces transcriptional repression through histone deacetylation. Binding of the ligand (RA) induces conformational changes and the binding of co-activators leading to histone acetylation and activation of transcription.
Figure 3. Phylogeny of deuterostome retinoic acid receptors (RARs). The tree shows the phylogenetic relationships between RARs from the sea urchin Strongylocentrotus purpuratus, the ascidian tunicate Ciona intestinalis, the cephalochordate Branchiostoma floridae, pufferfish (Takifugu rubripes) and humans (Homo sapiens). The RAR sequences were added to an alignment of nuclear hormone receptors 34 and conserved sites (335 positions) were subsequently selected for phylogenetic reconstruction using PhyML (WAG + Î8 + I) 61. 100 bootstrap replicates were carried out to determine the robustness of the obtained phylogenetic tree. In the tree, the RAR subfamily as a whole is strongly supported (bootstrap support 95%) and within the RARs the sea urchin sequence is at the base (with a moderate support of 70%). The respective branching of the cephalochordate and tunicate RARs is not resolved (bootstrap support of 49%). Nonetheless, the invertebrate chordate sequences are positioned between the sea urchin RAR and the duplicated RARs of vertebrates, which form a single clade that is very strongly supported (100%). This analysis shows that a RAR gene is present in the genome of echinoderms and suggests that, despite the lack of data from hemichordates, the presence of RAR is an ancestral character of deuterostomes.
Figure 4. RA signaling controls Hox1 expression in central nervous system (CNS) and general ectoderm of developing amphioxus. A) The rostral limit of Hox1 expression in the CNS (arrowheads) is shifted, respectively, anteriorly and posteriorly by 1x10-6M RA and 1x10-6M RA antagonist (BMS009). Side views of whole mounts of 20-hour amphioxus embryos with anterior to the left. Scale bar=50μm. âxâ shows the level of the frontal sections in B). B) In the general ectoderm, the rostral limit of Hox1 (arrowheads) is shifted anteriorly by 1x10-6M RA, whereas treatment with 1x10-6M RA antagonist (BMS009) downregulates Hox1 expression. Frontal sections of 20-hour amphioxus embryos with anterior to the left. Scale bar=50μm. Modified with permission from 52.
Figure 5. Evolution of RA- and Hox-dependent patterning mechanisms in deuterostomes. In scenario 1, the putative deuterostome ancestor had a central nervous system (CNS) (located ventrally) and both CNS and general ectoderm were patterned by Hox genes, while a role for RA signaling remains elusive. In this scenario, chordates evolved by dorso-ventral axis inversion and the CNS was secondarily lost in the hemichordate lineage. In scenario 2, the nervous system of the ancestral deuterostome was organized as an ectodermal nerve net. Hox-dependent patterning codes were present in the ectoderm, but again a role for RA signaling remains elusive. Early during chordate evolution, condensation of a central nervous system (CNS) dorsally led to the creation of two RA-Hox patterning hierarchies one in general ectoderm and one in neural ectoderm (i.e. in the CNS). In the vertebrate lineage, neural crest function was elaborated and neural crest cells contribute to patterning and development of the embryo by carrying positional information from the CNS into other tissues, for example in the pharyngeal region.
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