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Gene Review

Cxcl12  -  chemokine (C-X-C motif) ligand 12

Mus musculus

Synonyms: 12-O-tetradecanoylphorbol 13-acetate repressed protein 1, AI174028, C-X-C motif chemokine 12, PBSF, PBSF/SDF-1, ...
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Disease relevance of Cxcl12


High impact information on Cxcl12

  • Together, the data suggest a model for VEGF-programmed adult neovascularization highlighting the essential paracrine role of recruited myeloid cells and a role for SDF1 in their perivascular retention [7].
  • Pharmacological or genetic ablation of adrenergic neurotransmission indicates that norepinephrine (NE) signaling controls G-CSF-induced osteoblast suppression, bone CXCL12 downregulation, and HSPC mobilization [8].
  • BM ablation induces SDF-1, which upregulates MMP-9 expression, and causes shedding of sKitL and recruitment of c-Kit+ stem/progenitors [9].
  • FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release [1].
  • These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1 [5].

Chemical compound and disease context of Cxcl12


Biological context of Cxcl12

  • SDF-1 and its primary physiologic receptor CXCR4 have multiple essential functions in development including colonization of bone marrow by hematopoietic cells and neuron localization within cerebellum during embryogenesis as well as B lymphopoiesis and cardiovasculogenesis [11].
  • The amino acid sequence of this cytokine, designated pre-B-cell growth-stimulating factor (PBSF), revealed that it is a member of intercrine alpha subfamily [12].
  • The SDF-1/CXCR4 axis has been implicated in the chemotaxis, homing, mobilization, and expansion of hematopoietic stem and progenitor cells [3].
  • To the authors' knowledge, this is the first published report of disrupting the SDF-1 gradient between bone marrow and peripheral blood through a physiologically relevant mechanism, resulting in mobilization with kinetics similar to other mobilizing CXC chemokines [13].
  • Recent genetic evidence in zebrafish has shown that the interaction between stromal cell-derived factor 1 (SDF1) and its G-protein-coupled receptor CXCR4, already known to control many types of normal and pathological cell migrations, is also required for the normal migration of primordial germ cells [14].

Anatomical context of Cxcl12


Associations of Cxcl12 with chemical compounds

  • Instead, SDF-1 increases, uniquely associated with sulfated glycan-mobilizing treatments and not with several other mobilizing agents tested, are likely responsible [13].
  • Investigations designed to investigate whether CXCL12 can act as a chemoattractant demonstrated that cells dissociated from E17 or adult SVZ neurospheres migrated toward an CXCL12 gradient and this was blocked by the CXCR4 antagonist AMD3100 [15].
  • In addition, neurospheres grown from the subventricular zone (SVZ) of 4-week-old mice exhibited large increases in Ca(2+) in response to CXCL12 and several other chemokines [15].
  • In fetal liver, we identified Lin(-)CD19(-)c-kit(+)IL-7Ralpha(+)AA4.1(+), the earliest unipotent B cell precursor population, and found that its development was severely affected in SDF-1(-/-) embryos but not in IL-7(-/-) embryos [16].
  • Therefore, combined pretreatment with SDF-1 or TNF-alpha and expression of alpha4 integrin leads to massive colonization (>50%) followed by reconstitution of >80% of alpha-sarcoglycan-expressing fibers, with a fivefold increase in efficiency in comparison with control cells [17].
  • Preventing activation of the classic MAP kinase cascade with the Erk inhibitor UO126 abolished SDF1-induced proliferation and migration of C2C12 cells but not the inhibitory action of SDF1 on myogenic differentiation [18].

Physical interactions of Cxcl12

  • In summary, our findings unravel a previously unrecognized complex role of CXCL12/CXCR4 in the control of limb neuromuscular development [19].

Regulatory relationships of Cxcl12


Other interactions of Cxcl12

  • Genetic studies reveal that Cxcl12-Cxcr4 signaling directs the ventral trajectory of spinal vMNs [24].
  • 4F (SFT3) and 5F (4F + SDF-1) were the most efficient combinations (81.2% and 87.5%, respectively), which was better than 3F (SFT, 50%), TPO alone (58.3%), and SDF-1 alone (29.2%) and also better than 4F given at 10 microg/kg per injection (4F10, 45.8%) or as a 50 microg/kg single injection at 2 hours (4Fs, 62.5%) [25].
  • Altered thymocyte migration during experimental acute Trypanosoma cruzi infection: combined role of fibronectin and the chemokines CXCL12 and CCL4 [26].
  • CXCR4-expressing cells in the DG were found in close proximity to immature granule neurons that expressed the chemokine SDF-1/CXCL12 [27].
  • In BM, the levels of mRNAs for SCF and SDF-1 were increased and that for TGFbeta1 decreased at time intervals at which HPC are known to proliferate intensively during BM regeneration [28].

Analytical, diagnostic and therapeutic context of Cxcl12


  1. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Avecilla, S.T., Hattori, K., Heissig, B., Tejada, R., Liao, F., Shido, K., Jin, D.K., Dias, S., Zhang, F., Hartman, T.E., Hackett, N.R., Crystal, R.G., Witte, L., Hicklin, D.J., Bohlen, P., Eaton, D., Lyden, D., de Sauvage, F., Rafii, S. Nat. Med. (2004) [Pubmed]
  2. Molecular cloning and characterization of a murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin. Nagasawa, T., Nakajima, T., Tachibana, K., Iizasa, H., Bleul, C.C., Yoshie, O., Matsushima, K., Yoshida, N., Springer, T.A., Kishimoto, T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  3. Small peptide analogue of SDF-1alpha supports survival of cord blood CD34+ cells in synergy with other cytokines and enhances their ex vivo expansion and engraftment into nonobese diabetic/severe combined immunodeficient mice. Li, K., Chuen, C.K., Lee, S.M., Law, P., Fok, T.F., Ng, P.C., Li, C.K., Wong, D., Merzouk, A., Salari, H., Gu, G.J., Yuen, P.M. Stem Cells (2006) [Pubmed]
  4. CXCL12 mediates CCR7-independent homing of central memory cells, but not naive T cells, in peripheral lymph nodes. Scimone, M.L., Felbinger, T.W., Mazo, I.B., Stein, J.V., Von Andrian, U.H., Weninger, W. J. Exp. Med. (2004) [Pubmed]
  5. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Ceradini, D.J., Kulkarni, A.R., Callaghan, M.J., Tepper, O.M., Bastidas, N., Kleinman, M.E., Capla, J.M., Galiano, R.D., Levine, J.P., Gurtner, G.C. Nat. Med. (2004) [Pubmed]
  6. Identification of a transient subpial neurogenic zone in the developing dentate gyrus and its regulation by Cxcl12 and reelin signaling. Li, G., Kataoka, H., Coughlin, S.R., Pleasure, S.J. Development (2009) [Pubmed]
  7. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Grunewald, M., Avraham, I., Dor, Y., Bachar-Lustig, E., Itin, A., Yung, S., Chimenti, S., Landsman, L., Abramovitch, R., Keshet, E. Cell (2006) [Pubmed]
  8. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Katayama, Y., Battista, M., Kao, W.M., Hidalgo, A., Peired, A.J., Thomas, S.A., Frenette, P.S. Cell (2006) [Pubmed]
  9. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N.R., Crystal, R.G., Besmer, P., Lyden, D., Moore, M.A., Werb, Z., Rafii, S. Cell (2002) [Pubmed]
  10. Stromal cell-derived factor-1-induced LFA-1 activation during in vivo migration of T cell hybridoma cells requires Gq/11, RhoA, and myosin, as well as Gi and Cdc42. Soede, R.D., Zeelenberg, I.S., Wijnands, Y.M., Kamp, M., Roos, E. J. Immunol. (2001) [Pubmed]
  11. Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1). Ara, T., Nakamura, Y., Egawa, T., Sugiyama, T., Abe, K., Kishimoto, T., Matsui, Y., Nagasawa, T. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  12. Molecular cloning and structure of a pre-B-cell growth-stimulating factor. Nagasawa, T., Kikutani, H., Kishimoto, T. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  13. Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Sweeney, E.A., Lortat-Jacob, H., Priestley, G.V., Nakamoto, B., Papayannopoulou, T. Blood (2002) [Pubmed]
  14. The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Molyneaux, K.A., Zinszner, H., Kunwar, P.S., Schaible, K., Stebler, J., Sunshine, M.J., O'Brien, W., Raz, E., Littman, D., Wylie, C., Lehmann, R. Development (2003) [Pubmed]
  15. Chemokine receptors are expressed widely by embryonic and adult neural progenitor cells. Tran, P.B., Ren, D., Veldhouse, T.J., Miller, R.J. J. Neurosci. Res. (2004) [Pubmed]
  16. The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor. Egawa, T., Kawabata, K., Kawamoto, H., Amada, K., Okamoto, R., Fujii, N., Kishimoto, T., Katsura, Y., Nagasawa, T. Immunity (2001) [Pubmed]
  17. Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability. Galvez, B.G., Sampaolesi, M., Brunelli, S., Covarello, D., Gavina, M., Rossi, B., Costantin, G., Torrente, Y., Cossu, G. J. Cell Biol. (2006) [Pubmed]
  18. The chemokine SDF1 controls multiple steps of myogenesis through atypical PKCzeta. Odemis, V., Boosmann, K., Dieterlen, M.T., Engele, J. J. Cell. Sci. (2007) [Pubmed]
  19. Mice deficient in the chemokine receptor CXCR4 exhibit impaired limb innervation and myogenesis. Odemis, V., Lamp, E., Pezeshki, G., Moepps, B., Schilling, K., Gierschik, P., Littman, D.R., Engele, J. Mol. Cell. Neurosci. (2005) [Pubmed]
  20. Syngenic bone marrow cells restore hepatic function in carbon tetrachloride-induced mouse liver injury. Jung, Y.J., Ryu, K.H., Cho, S.J., Woo, S.Y., Seoh, J.Y., Chun, C.H., Yoo, K., Moon, I.H., Han, H.S. Stem Cells Dev. (2006) [Pubmed]
  21. Embryonic expression and function of the chemokine SDF-1 and its receptor, CXCR4. McGrath, K.E., Koniski, A.D., Maltby, K.M., McGann, J.K., Palis, J. Dev. Biol. (1999) [Pubmed]
  22. TNF-alpha mediates SDF-1 alpha-induced NF-kappa B activation and cytotoxic effects in primary astrocytes. Han, Y., He, T., Huang, D.R., Pardo, C.A., Ransohoff, R.M. J. Clin. Invest. (2001) [Pubmed]
  23. Stromal cell-derived factor-1 (SDF-1) recruits osteoclast precursors by inducing chemotaxis, matrix metalloproteinase-9 (MMP-9) activity, and collagen transmigration. Yu, X., Huang, Y., Collin-Osdoby, P., Osdoby, P. J. Bone Miner. Res. (2003) [Pubmed]
  24. A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Lieberam, I., Agalliu, D., Nagasawa, T., Ericson, J., Jessell, T.M. Neuron (2005) [Pubmed]
  25. Short-term injection of antiapoptotic cytokine combinations soon after lethal gamma -irradiation promotes survival. Hérodin, F., Bourin, P., Mayol, J.F., Lataillade, J.J., Drouet, M. Blood (2003) [Pubmed]
  26. Altered thymocyte migration during experimental acute Trypanosoma cruzi infection: combined role of fibronectin and the chemokines CXCL12 and CCL4. Mendes-da-Cruz, D.A., Silva, J.S., Cotta-de-Almeida, V., Savino, W. Eur. J. Immunol. (2006) [Pubmed]
  27. Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brain. Tran, P.B., Banisadr, G., Ren, D., Chenn, A., Miller, R.J. J. Comp. Neurol. (2007) [Pubmed]
  28. Cytokine gene expression in regenerating haematopoietic tissues of mice after cyclophosphamide treatment. Psenák, O., Sefc, L., Sýkora, V., Chang, K.T., Necas, E. Acta Haematol. (2003) [Pubmed]
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