Cytokines & Cells Online Pathfinder Encyclopaedia
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[Stromal cell-derived factor] SDF-1-alpha and SDF-1-beta are small cytokines belonging to the CXC-Chemokines. The factors have been referred to also as TLSF-alpha [Thymic lymphoma cell stimulating factor-alpha] and TLSF-beta [Thymic lymphoma cell stimulating factor-beta]. The protein is identical also with TPA repressed gene-1. According to a new systematic nomenclature the name CXCL12 has been proposed for this factor. The gene symbol is SCYB12. This factor is known mainly because of its chemotactic activity. For an unrelated function as an antimicrobial peptide in innate immunity see: CXCL12.
SDF-1 is identical with a chemokine reported to function as a pre-B-cell growth factor in the presence of IL7 and isolated originally from a murine bone marrow stromal cell line (see: PBSF). It is identical also with IRH [intercrine reduced in hepatomas].
SDF-1(5-67) is obtained by removal of an N-terminal tetrapeptide by cleavage with active MMP-2. Zhang et al (2003) have reported that implantation of cleaved chemokine into the basal ganglia of mice results in neuronal cell death by apoptosis and inflammation with ensuing neurobehavioral deficits.
The cDNAs of murine SDF-1-alpha and SDF-1-beta encode proteins of 89 and 93 amino acids, respectively. The amino acid sequences are identical but differ by the presence of an additional 4 amino acids at the C-terminus of SDF-1-beta. SDF-1-alpha and SDF-1-beta sequences are more than 92 % identical with those of the human counterparts. Human SDF-1-alpha and SDF-1-beta are encoded by a single gene and arise by alternative splicing. The human SDF-1 gene is located on chromosome 10q11.1 close to the ret proto-oncogene locus. Peptides corresponding to the N-terminal 9 residues of the factor have been shown to possess activities similar to SDF-1 although the peptides were less potent.
The SDF-1 gene is expressed ubiquitously with the exception of blood cells. SDF-1 acts on lymphocytes and monocytes but not neutrophils in vitro and is a highly potent chemoattractant for mononuclear cells in vivo. In addition. SDF-1 also induces intracellular actin polymerization in lymphocytes. Bleul et al (1996) have identified a lymphocyte chemotactic activity in the conditioned medium of the murine bone marrow stroma cell line MS-5. This factor is identical with SDF-1.
In vitro and in vivo, SDF acts as a chemoattractant (see also: Chemotaxis) for human hematopoietic progenitor cells expressing CD34 (BFU-E, CFU-GM, CFU, giving rise to mixed types of progenitors, and more primitive types; see also: hematopoiesis). The chemotactic response is inhibited by pertussis toxin. Chemotaxis of CD34(+) cells in response to SDF is increased by IL3 in vitro. SDF has been shown also to induce a transient elevation of cytoplasmic calcium in these cells.
Like some chemokines, and unlike other chemokines, that do, SDF-1 does not possess suppressive activity against immature subsets of myeloid progenitors (see also: hematopoiesis) stimulated to proliferate by multiple growth factors (Broxmeyer et al, 1999).
SDF-1-alpha, through interactions with its receptor CXCR4 can directly induce cell death by apoptosis in the human hNT neuronal cell line, which resembles immature post-mitotic cholinergic neurons and has a number of neuronal characteristics (Hesselgesser et al, 1998).
SDF-1-gamma is an SDF-1 isoform isolated from the rat. In the rat, neurons and Schwann cells are the main cellular sources of both SDF-1-beta and SDF-1-gamma mRNAs. SDF-1-beta-mRNA is the predominant isoform in embryonic and early postnatal nerve tissue. SDF-1-gamma mRNA is expressed at higher levels in adulthood. After peripheral nerve lesion a transient increase in SDF-1-beta mRNA expression is observed. Muller et al (2001) have described the development of multi-probe RNase protection assay (RPA) template sets for the simultaneous analysis of several chemokines, including SDF-1-gamma.
Ma et al (1998) have studied knock-out mice lacking expression of SDF-1. These animals die perinatally, showing severely reduced development of B-cells, reduced myelopoiesis in fetal liver, and a virtual absence of myelopoiesis in bone marrow (see also: hematopoiesis). The development of T-cells is not affected. In addition, the cerebellum develops abnormally with an irregular external granule cell layer, ectopically located Purkinje cells, and numerous chromophilic cell clumps of abnormally migrated granule cells within the cerebellar anlage. Identical defects are observed in mice lacking the SDF-1 receptor, CXCR4 ligand.
RECEPTORS
The cDNA for SDF receptor was isolated from a murine pre B-cell line, DW34. It encodes a seven transmembrane spanning domain receptor, designated Pre-B-cell derived chemokine receptor (PB-CKR). The deduced amino acid sequence shows 90 % identity with Fusin, which functions as a human coreceptor for HIV 1 (see: CXCR4). Murine SDF-1 has been shown to induce calcium influx in CHO cells transfected with Fusin. SDF-1-alpha has been shown to bind to the virus-encoded viroceptor M3 and to vGPCR. An other receptor, RDC1 on T-cells has been identified by Balabanian et al (2005)
TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES
The biological consequences of an SDF gene disruption have been studied in transgenic knock-out mice carrying a targeted deletion of the gene. The animals die perinatally. The number of hematopoietic progenitor cells (CFC-Mix, CFU-GM, CFU-IL7) are greatly reduced in bone marrow.
Myelopoiesis and B-cell lymphopoiesis in the bone marrow is eliminated. The factor is required for myelopoiesis in the bone marrow but not in the fetal liver. In addition, SDF function is not limited to the hematopoietic system. Animals lacking SDF have been shown to suffer from a ventricular septum defect. The same defect is observed also in animals deficient in endothelin-1 and in animals deficient of the retinoic acid receptor-alpha. It is not clear, however, how these factors cooperate in the formation of the ventricular septum.
LAST MODIFIED: January 2003
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