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In contrast to chordates authentic chemokine and receptor or
As one of the two receptors for the primordial chemokine CXCL12, ACKR3 exists in jawless fish (Bajoghli, 2013, Nomiyama et al., 2011, Venkatesh et al., 2014). The sea lamprey genome contains two copies of the ACKR3 gene (Ensembl Acc. Nos.: ENSPMAP00000011187 and ENSPMAP00000011401) (Table 1), both encoded by a single exon. The ACKR3b gene is clustered with the IQCA1 gene in Scaffold_GL478568 (Fig. 3) whilst the CXCR3a is located at a different scaffold (scaffold: GL476634). The chromosomal locations of the two scaffolds and divergence of the two genes have not been resolved. It is not clear whether they have been duplicated from a common gene, either by a whole genome duplication (Caputo Barucchi et al., 2013, Mehta et al., 2013) or a lineage-specific duplication event as seen for the Hox gene family (Force et al., 2002). The genomic clustering of the ACKR3/CXCR7 gene with IQCA1 is conserved among all jawed vertebrates examined (Fig. 3), with a single ACKR3/CXCR7 gene present in most vertebrate groups including cartilaginous fish, some Tivantinib groups (e.g. Holostei and Sarcopterygii) and tetrapods but duplicated copies in the teleost lineage. This strongly suggests a common origin of ACKR3/CXCR7 genes in the ancient genomes.
ACKR1/DARC is distantly related to other chemokine receptors and is expressed primarily in red blood cells and endothelial cells. It binds to a number of inflammatory chemokines including CXCL1, CXCL5–9, CXCL11 and CXCL13, and is suggested to play a role in maintaining chemokine levels in the blood (Dawson et al., 2000). ACKR1 has been identified only in amniotes to date, and thus is likely to have arisen relatively late in vertebrate evolution (Nomiyama et al., 2011).
ACKR2/CCBP2 principally interacts with several homeostatic and inflammatory CC chemokines (Bachelerie et al., 2014). It shares high sequence homology with CCR8 and its expression can be detected in skin, gut, lung and placenta and is believed to act as a suppressive receptor for controlling excessive inflammation in mucosal tissues (Nibbs et al., 2001). A single copy of the ACKR2 gene has been found in jawed vertebrates including the teleost lineage (Table 2).
ACKR4 is an atypical receptor for homeostatic CC and CXC chemokines including CCL19, CCL21, CCL25 and CXCL13 (Comerford et al., 2006). However, a recent study has demonstrated that human ACKR4 is also able to antagonise CXCR3-induced chemotaxis through heterodimer formation with the signalling receptor CXCR3 (Vinet et al., 2013). In teleost fish, two ACKR4s (ACKR4a/CCRL1 and ACKR4b/CCRL2) have been sequenced and are closely related to CCR6, 7, 9 and 10 (Liu et al., 2009, Nomiyama et al., 2011). Similar to teleost ACKR3s/CXCR7s, one of the two ACKR4as/CCRL1s appears to be teleost specific. A single copy of ACKR4a/CCRL1 has recently been reported in the elephant shark (Venkatesh et al., 2014). However, the expression and functions of fish ACKRs have not been determined. Liu et al. reported the expression of ACKR4a/CCRL1–1 during embryo development in zebrafish (Liu et al., 2009) but in a separate study ACKR4a/CCRL1–1 transcripts were not detectable by in situ hybridisation during embryogenesis in medaka (Aghaallaei et al., 2010).


Origin of vertebrate CXC chemokine receptors
The evolution of the vertebrate CXC chemokines and receptors has not been resolved. Based on the evolution of the immune system and central nervous system, Huising et al. proposed that primordial CXC chemokines and receptors developed first as regulators of neuron chemotaxis (Huising et al., 2003a) and have identified CXCL12/CXCR4 as the possible primordial molecules. This theory has been disputed by others because the CXCL12/CXCR4 orthologues are not found in the primitive chordate species such as amphioxus (Branchiostoma floridae) and sea squirt (Ciona intestinalis) which possess a central nerve system (Bajoghli, 2013, Holland, 2009, Nomiyama et al., 2011, Shields, 2003).
After extensive sequence analysis, we found that three database entries (Ensembl Acc. Nos.: ENSCINP00000026710, ENSCINP00000013105 and ENSCINP00000030444) with moderate sequence homology to vertebrate chemokine receptors are present in the C. intestinalis genome (Table 2 and Supplementary file 5). Blastp analysis of these sequences gave top hits with relaxin/insulin-like family peptide receptor (RXFP) 3, angiotensin II receptor (AGTR), somatostatin receptor (SSTR), CCR and CXCR, suggesting a possible common origin. RXFP3, AGTR and SSTR bind to neuron-endocrine peptide ligands and regulate many physiological processes in animals, including reproduction, growth, the nervous system, food intake, inflammation and stress (Bathgate et al., 2013, Ferrario and Strawn, 2006, Tulipano and Schulz, 2007). It is notable that two of the three C. intestinalis molecules (Ensembl Acc. Nos.: ENSCINP00000013105 and ENSCINP00000030444) contain a DRY motif (DRWLAIV and DRYLAVV respectively) that is conserved in some GPCRs including chemokine receptors (Fig. 5). This motif is known to be required for G-protein coupling and downstream signalling (Graham et al., 2012, Wu et al., 2010). Intriguingly, the C. intestinalis RXFP3 orthologue also possesses the DRY motif (DRYMAVV, Fig. 5). Furthermore, chemokine receptors and some members of the RXFP3 and AGTR family members share cellular components such as arrestins, PI3K and extracellular regulated MAP kinase (ERK) 1/2 for signal transduction (Bathgate et al., 2013, van der Westhuizen et al., 2007). It is believed that the relaxin 3/RXFP3 system pre-dates the appearance of the chemokine system (Bathgate et al., 2013), and in humans CXCR4, ACKR3/CXCR7, CCR1 and CCR9 have been shown to be related to RXFP3 and RXFP4, AGTR, and formyl peptide receptors (FPR2 and FPR3) (Bathgate et al., 2013).
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