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Molecular Evolution of Peptidergic Signaling Systems in Bilaterians

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Molecular Evolution of Peptidergic Signaling Systems in Bilaterians Molecular evolution of peptidergic signaling systems in bilaterians Olivier Mirabeau1 and Jean-Stéphane Joly Unité propre de Recherche 3294, Neurobiology and Development Research Unit, Institut Fessard, Centre National de la Recherche Scientifique and Institut National de la Recherche Agronomique, 91198 Gif-sur-Yvette, France Edited by John Gerhart, University of California, Berkeley, CA, and approved April 12, 2013 (received for review November 25, 2012) Peptide hormones and their receptors are widespread in metazo- atode Caenorhabditis elegans (12), and the mosquito Anopheles ans, but the knowledge we have of their evolutionary relationships gambiae (13). In these species, original genome-wide searches remains unclear. Recently, accumulating genome sequences from have revealed the existence of a large number of GPCRs that many different species have offered the opportunity to reassess resembled vertebrate GPCRs (11), but comparatively few ver- the relationships between protostomian and deuterostomian pepti- tebrate-type peptides (11, 12, 14). dergic systems (PSs). Here we used sequences of all human rhodopsin Before the genomic era, some researchers had postulated a and secretin-type G protein-coupled receptors as bait to retrieve deep orthology between PSs from distant animals on the basis of potential homologs in the genomes of 15 bilaterian species, in- peptide primary sequence similarity (15), functional analogies cluding nonchordate deuterostomian and lophotrochozoan spe- (16), and immunoreactivity of invertebrate tissues to mammalian cies. Our phylogenetic analysis of these receptors revealed 29 well- hormone antibodies (17), but the idea that it could be a general supported subtrees containing mixed sets of protostomian and feature of PSs remained controversial. Now, with the accumu- deuterostomian sequences. This indicated that many vertebrate lation of molecular sequence data and the characterization of and arthropod PSs that were previously thought to be phyla a growing number of PSs from insects and mammals, the concept fi speci c are in fact of bilaterian origin. By screening sequence data- of a bona fide orthology between protostome and deuterostome bases for potential peptides, we then reconstructed entire bilat- PSs has garnered new support (18, 19). Recently, Schoofs and erian peptide families and showed that protostomian and deu- coworkers have added new weight to this theory by showing that terostomian peptides that are ligands of orthologous receptors some arthropod-type PSs [adipokinetic hormone (AKH), pyro- displayed some similarity at the level of their primary sequence, kinin (PK), and sulfakinin (SK)] occurring in C. elegans were suggesting an ancient coevolution between peptide and receptor orthologous to vertebrate PSs [gonadoliberin (GnRH), neuro- genes. In addition to shedding light on the function of human G medin U (NMU), and cholecystokinin (CCK)] (20–22). protein-coupled receptor PSs, this work presents orthology markers In an effort to clarify the relationships between protostomian to study ancestral neuron types that were probably present in the and deuterostomian PSs, we set out to reconstruct the full evo- last common bilaterian ancestor. lutionary history of bilaterian peptide and receptor genes. We neuropeptide evolution | GPCR evolution | bilaterian CNS cell types | used data from publicly available genomes from Ensembl (23), bilaterian brain evolution the Joint Genome Institute (JGI) (24), the Ghost database (25), and the Baylor College of Medicine (BCM), including data from key lophotrochozoan and ambulacrarian phyla that are thought to n animals the regulation of complex homeostatic processes and have retained ancestral features of the bilaterian brain (26–28). Itheir behavioral output relies on the modulation of neuronal fi We performed phylogenetic reconstructions (29, 30) and used activity in well-de ned circuits of the brain. Groups of neurons a hidden Markov model (HMM)-based program, which predicts can influence the activity of other groups of neurons by releasing precursor hormone sequences (31). in the extracellular milieu short peptide hormones, called neu- Our analysis suggests that 29 PSs were present in the last ropeptides, which, with few exceptions, notably insulin-like pep- common ancestor of bilaterians (the urbilaterian) and that, in the tides, bind G protein-coupled receptors (GPCRs) that are expressed at the surface of target cells. GPCRs are seven-pass Significance membrane receptors that can bind to a wide variety of ligands (1) and form the largest family of integral membrane proteins in the fi human genome (2). The majority of GPCRs that are activated by Peptides and their speci c receptors form molecular peptider- peptide ligands are thought to be evolutionarily related and gic systems (PSs) that are essential components of neuronal belong to the rhodopsin β and γ classes of rhodopsin (r) communication in the animal brain. Many PSs have been char- GPCRs, or to the secretin (s) family of GPCRs (3). Peptides are acterized in insects and mammals but their precise evolutionary short (<40 amino acids) secreted polypeptides derived from relationship is not fully understood. We interrogated genomic larger precursor proteins that are encoded by the genome and sequence databases and used phylogenetic reconstruction tools fi to show that a large fraction of human PSs were already pres- processed by specialized enzymes (4). They share de ning features fl at the level of their primary sequence, including the presence of ent in the last common ancestor of ies, mollusks, urchins, and mammals. Our analysis provides a comprehensive view of ani- signal peptides at their N terminus, of canonical dibasic processing mal PSs that will pave the way for comparative studies leading sites that are recognized by prohormone convertase cleaving to a better understanding of animal physiology and behavior. enzymes (5), and of a C-terminal glycine that is the target of amidation enzymes (6). Author contributions: O.M. and J.-S.J. designed research; O.M. performed research; O.M. Research on peptide hormones has a long history (7, 8), and contributed new reagents/analytic tools; O.M. analyzed data; and O.M. and J.-S.J. wrote during the last decades a substantial number of peptide–recep- the paper. tors systems, or peptidergic systems (PSs), have been charac- The authors declare no conflict of interest. terized by reverse pharmacology methods in both insects (9) and This article is a PNAS Direct Submission. mammals (10). In parallel, the first genome sequencing projects 1To whom correspondence should be addressed. E-mail: [email protected]. have enhanced our knowledge of PS diversity in protostomian This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. species, notably in the fly Drosophila melanogaster (11), the nem- 1073/pnas.1219956110/-/DCSupplemental. E2028–E2037 | PNAS | Published online May 13, 2013 www.pnas.org/cgi/doi/10.1073/pnas.1219956110 Downloaded by guest on September 27, 2021 PNAS PLUS general case, peptide and receptor genes coevolved in the dif- members of AncBILAT suggest that gene members of several ferent lineages leading to present-day bilaterians. We present a bilaterian subtrees including neuropeptide S (NPS)-R/crustacean comprehensive list of PSs that are common to bilaterian species, cardioactive peptide (CCAP)-R, neuropeptide FF (NPFF)-R/ so that these orthology markers can be used to reveal the origin SIF-amide (SIFa)-R, ecdysis-triggering hormone (ETH)-R, CCK- and function of ancient peptidergic cell types and circuits. All R/SK-R, GnRH-R/AKH-R, tachykinin-R (TKR), orexin (Ox)-R/ sequences, phylogenetic trees, and annotations derived from allatotropin (AT)-R, vasopressin (AVP)-R, and leucokinin (LK)-R these analyses can be found at http://neuroevo.org. share orthologous introns (Fig. 3) and are likely to have evolved from a common ancestral bilaterian receptor gene. In all abbre- Results viations of protein names the suffix R stands for receptor. Note Phylogenetic Analysis of Bilaterian Receptors Reveals Ancestral Recep- that because all of these receptors are members of a family, we tors. By following the strategy described in Fig. 1A (Methods)we chose to use the name of one of the members to designate the were able to retrieve a set of 592 bilaterian β rGPCRs, 166 bilat- group of closely related receptors [e.g., “arginine-vasopressin erian γ rGPCRs, and 115 sGPCRs. Maximum likelihood phylo- receptor” (AVPR) was used to denominate both vasopressin and genetic analysis with SH-like likelihood ratio tests (LRTs) as branch oxytocin receptors]. support values (Methods) applied to β rGPCRs (respectively γ rGPCRs and sGPCRs) revealed, to our surprise, 22 (respectively Ligands from Orthologous Receptors Are Orthologous Peptides. We next used our receptor orthology hypotheses as a guide to derive 2 and 5) well-supported subtrees, denoted AncBILAT, that con- tained a diversified set of deuterostome and protostome GPCRs, orthology hypotheses for peptides and reconstruct bilaterian, suggesting that the receptors forming these subtrees evolved from protostomian, deuterostomian, and chordate alignments of ho- mologous peptides (Dataset S1). For that we first screened distinct ancestral bilaterian receptors (Fig. 2). public databases for the presence of putative peptide precursor To test whether these associations of protostomian and deu- sequences using an HMM-based program (Methods and Fig. 1B). terostomian peptidergic GPCRs were statistically
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