The CXCL12 gene consists of 4 exons spanning 14.94 kb on the chromosome 10 at band q11.21 (reverse strand) (Figure 1).

Alternative splicing results in eight transcript variants (Table 1), as shown in Ensembl database. Among them, six correspond to as many protein isoforms (Yu et al., 2006).

No known pseudogenes.

CXCL12 gene encodes a stromal cell-derived alpha chemokine, also known as SDF1, a member of the intercrine family. This family is defined by the location of the first two cysteine residues in the sequence, which are separated by one amino acid (C-X-C chemokine)(Hromas, 1997). Six protein isoforms have been identified in human: Alpha, Beta, Gamma, Delta, Epsilon and Theta (Table 2; Figure 2), produced by alternative splicing events (Yu et al., 2006). In particular Alpha and Beta isoforms, secreted as full-length molecules, undergo to post-translational modifications by a proteolytic cleavage, becoming respectively processed forms SDF-1-alpha(3-67) and SDF-1-beta(3-72)(De la Luz Sierra et al., 2004). The Beta isoform has been chosen as the canonical sequence and, together with Alpha isoform, is ubiquitously expressed in liver, pancreas and spleen. The Gamma Isoform is mainly expressed in heart, while the isoforms Delta, Epsilon and Theta are mainly expressed in pancreas. In the developmental stage, the isoform Alpha is ubiquitously expressed in fetal tissues, Beta and Delta isoforms in fetal spleen and liver, while Gamma and Theta isoforms are weakly detected in fetal kidney (Yu et al., 2006).

CXCL12 is widely expressed in a variety of tissue types, such as heart, liver, spleen, kidney, brain, skeletal muscle, endothelium, epithelium, lymphoid organs, stem cells as well as overexpressed in cancer cells (Kryczek et al., 2007; Teicher and Fricker, 2010).

Extracellular region.

The CXCL12 protein functions as a ligand for two seven-transmembrane receptors (7-TMRs). The first one is the chemokine (C-X-C motif) receptor 4 (CXCR4), a monogamous receptor that signals through heterotrimeric G proteins and beta-arrestin; the second one is the chemokine (C-X-C motif) receptor 7 (CXCR7), a non-monogamous receptor that does not activate G-protein-mediated signal transduction but signals only through beta-arrestin (Oberlin et al., 1996; Rajagopal et al., 2010; Sun et al., 2010; Zhu et al., 2012; Sanchez-Martin et al., 2013). In particular, CXCL12 has a higher affinity of binding to CXCR7 than to CXCR4 (Zhu et al., 2012), even if its affinity to CXCR7 seems to be reduced by the expression of CXCR4 at the membrane (Sanchez-Martin et al., 2013). CXCL12 is secreted in the extracellular space as monomeric and dimeric forms, which can trigger different effects on cell signaling (Ray et al., 2012). In fact, whereas CXCR4 binds both monomeric and dimeric forms, CXCR7 binds preferentially the dimeric one (Sanchez-Martin et al., 2013). For example, dimeric CXCL12 form induces calcium mobilization but fails to promote chemotaxis, which is induced by the monomer-based interactions (Ray et al., 2012; Sanchez-Martin et al., 2013). Many others cellular functions depend on CXCL12 activity, including embryogenesis, apoptosis and survival, immune response, tissue homeostasis, angiogenesis, calcium ion homeostasis, clathrin-mediated endocytosis, cytoskeletal rearrangement, cell proliferation and migration, tumor growth and metastasis (Vlahakis et al., 2002; Goda et al., 2006; Petit et al., 2007; Khan et al., 2008; Agle et al., 2010; Drury et al.,2010; Karin, 2010; Kremer, 2010; Sun et al., 2010; Zhu et al., 2012).

The CXCL12 Gene Tree shows a great evolutionary conservation across species (Figure 3). The internal nodes of the phylogenetic tree are annotated for duplication (red boxes) and speciation (blue boxes) events, which correspond to paralogs and orthologs homologous genes respectively.

NOTE It has been suggested that a single nucleotide polymorphism (SNP)in the 3 untranslated region of SDF-1-beta transcript is associated not only with a delayed onset (Winkler et al., 1998) and a modest protective effect against infection and progression of AIDS (Modi et al., 2005), but also with the early onset of type 1 diabetes (Dubois-Laforgue et al., 2001) and with an increased likelihood of developing several cancers (as lung, breast, colorectal and prostate)(Ma et al., 2012; Shi et al., 2013). This could be explained by an increased level and stability of SDF-1-beta transcript as effect of this mutation (Garcia-Moruja et al., 2009).

A SNP consisting of a G-to-A transition at position 801, counting from the ATG start codon in the 3 UTR of the Genbank reference sequence L36033, was represented in the SDF-1-beta transcript but not in the SDF-1-alpha transcript (Winkler et al., 1998). The mutation CXCL12-G801A-3 Prime UTR, also known as SDF1-3-prime-A, located at chromosome 10 position 44873550 on Assembly GRCh37, has been classified as pathogenic variant (dbSNP: rs387906400)related to the phenotype Human immunodeficiency virus type 1, resistance to (OMIM: 600835.0001).