br CXCR Among the CXCRs CXCR is the

CXCR4 Among the CXCRs, CXCR4 is the most well studied receptor owing to its critical roles in development. CXCR4 has been discovered as a single copy gene in agnathan and gnathostome vertebrates except for teleosts where duplicated CXCR4 (CXCR4a and 4b), and their ligands CXCL12 (CXCL12a and 12b), are present (Bajoghli, 2013, Baoprasertkul et al., 2005, Chen et al., 2013, DeVries et al., 2006, Huising et al., 2004, Nomiyama et al., 2011, Zlotnik et al., 2006). After binding to CXCL12 (also referred to as SDF-1), CXCR4 functions in a variety of biological processes during development, the immune response and disease. For example, in humans, CXCR4 as well as CXCR5 and CXCR6/Bonzo have been identified as co-receptors of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) for entry into the host carboxypeptidase (Feng et al., 1996, Kanbe et al., 1999, Matloubian et al., 2000). The CXCL12/CXCR4 ligand/receptor system is believed to be the most ancient chemokine system in vertebrates (Bajoghli, 2013, Huising et al., 2003a, Kuroda et al., 2003). Most data regarding fish CXCR4 functions have accumulated from work in zebrafish where a range of genetic tools and imaging technologies have been developed. As mentioned above, in teleost fish the two CXCR4s (CXCR4a and 4b) are assumed to interact with two ligands (CXCL12a and 12b) and this different pairing of ligands/receptors appears to effect different functions in regulating development of organs. In zebrafish, interaction between CXCL12a and CXCR4b is essential to guide migration of germ cells during embryogenesis, whilst the CXCL12b–CXCR4a axis controls directional migration of the endoderm during zebrafish gastrulation (Mizoguchi et al., 2008, Nair and Schilling, 2008). Depletion of CXCR4a expression causes separation of the endoderm from the mesoderm. CXCR4b signalling also mediates migration of primordial germ cells toward the location of the prospective gonadal primordium in zebrafish and medaka (Doitsidou et al., 2002, Herpin et al., 2008). Activation of CXCR4 requires phosphorylation of the intracellular C terminal region of the receptor, resulting in recruitment of regulatory proteins (Roland et al., 2003, Ueda et al., 2006). Interestingly, it has been shown recently that a Hox homeobox gene (Hoxb8a), best known for its role in axial patterning during development, plays a role in the modulation of CXCR4b and CXCR7b expression (Breau et al., 2013). CXCR4 is widely expressed in the central nervous system and its roles in neuron development and function have been well documented in mammals and, more recently, in bony fish. Most CXCR4-expressing ganglia progenitors differentiate to form sensory neurons and CXCL12a/SDF-1a–CXCR4b signalling is critical for directing neurons to reach the site of ganglion assembly and the development of the lateral line sensory system in zebrafish (Li et al., 2004). CXCR4 influences the migration of microglia to sites of brain injury in zebrafish and aids the wound healing process (Chuang et al., 2013). Knockdown of CXCR4b expression in zebrafish leads to abnormal GnRH3 axonal projections and cell migration (Palevitch et al., 2010). In addition, CXCR4 affects regeneration and heart functions (Itou et al., 2012), retinal growth (Li et al., 2005) and muscle myogenesis (Chong et al., 2007). It is highly expressed in human cancer cells and is often used as a biomarker in cancer diagnosis (Cabioglu et al., 2005).