Chemokines and their receptors are important in cell migration during inflammation1, in the establishment of functional lymphoid microenvironments2, and in organogenesis3. The chemokine receptor CXCR4 is broadly expressed in cells of both the immune and the central nervous systems4,5 and can mediate migration of resting leukocytes and haematopoietic progenitors in response to its ligand, SDF-1 (6–9). CXCR4 is also a major receptor for strains of human immunodeficiency virus-1 (HIV-1) that arise during progression to immunodeficiency and AIDS dementia10. Here we show that mice lacking CXCR4 exhibit haematopoietic and cardiac defects identical to those of SDF-1-deficient mice3, indicating that CXCR4 may be the only receptor for SDF-1. Furthermore, fetal cerebellar development in mutant animals is markedly different from that in wild-type animals, with many proliferating granule cells invading the cerebellar anlage. This is, to our knowledge, the first demonstration of the involvement of a G-protein-coupled chemokine receptor in neuronal cell migration and patterning in the central nervous system. These results may be important for designing strategies to block HIV entry into cells and for understanding mechanisms of pathogenesis in AIDS dementia.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Murphy, P. M. Chemokine receptors: structure, function and role in microbial pathogenesis. Cytokine Growth Factor Rev. 7, 47–64 (1996).
Förster, R.et al. Aputative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996).
Nagasawa, T.et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996).
Moepps, B., Frodl, R., Rodewald, H. R., Baggiolini, M. & Gierschik, P. Two murine homologues of the human chemokine receptor CXCR4 mediating stromal cell-derived factor 1alpha activation of Gi2 are differentially expressed in vivo. Eur. J. Immunol. 27, 2102–2112 (1997).
Jazin, E. E., Soderstrom, S., Ebendal, T. & Larhammar, D. Embryonic expression of the mRNA for the rat homologue of the fusin/CXCR-4 HIV-1 co-receptor. J. Neuroimmunol. 79, 148–154 (1997).
Oberlin, E.et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833–835 (1996).
Bleul, C. C.et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833 (1996).
Aiuti, A., Webb, I. J., Bleul, C., Springer, T. & Gutierrez-Ramos, J. C. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J. Exp. Med. 185, 111–120 (1997).
Bleul, C. C., Fuhlbrigge, R. C., Casasnovas, J. M., Aiuti, A. & Springer, T. A. Ahighly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J. Exp. Med. 184, 1101–1109 (1996).
Feng, Y., Broder, C. C., Kennedy, P. E. & Berger, E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G-protein-coupled receptor. Science 272, 872–877 (1996).
Hardy, R. R., Carmack, C. E., Shinton, S. A., Kemp, J. D. & Hayakawa, K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 173, 1213–1225 (1991).
Hayashi, S.et al. Stepwise progression of B lineage differentiation supported by interleukin 7 and other stromal cell molecules. J. Exp. Med. 171, 1683–1695 (1990).
Delassus, S. & Cumano, A. Circulation of hematopoietic progenitors in the mouse embryo. Immunity 4, 97–106 (1996).
Chaffin, K. E.et al. Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase. EMBO J. 9, 3821–9829 (1990).
Rudolph, U.et al. Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice. Nature Genet. 10, 143–150 (1995).
Akazawa, C., Ishibashi, M., Shimizu, C., Nakanishi, S. & Kageyama, R. Amammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal is a positive transcriptional regulator expressed in the developing nervous system. J. Biol. Chem. 270, 8730–8738 (1995).
Hatten, M. E. The role of migration in central nervous system neuronal development. Curr. Opin. Neurobiol. 3, 38–44 (1993).
Hatten, M. E. & Heintz, N. Mechanisms of neural patterning and specification in the developing cerebellum. Annu. Rev. Neurosci. 18, 385–408 (1995).
Feng, L., Hatten, M. E. & Heitz, N. Brain lipid-binding protein (BLBP): a novel signaling system in the developing mammalian CNS. Neuron 12, 895–908 (1994).
Springer, T. A. Adhesion receptors of the immune system. Nature 346, 425–434 (1990).
Campbell, J. J.et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381–384 (1998).
Serafini, T.et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87, 1001–1014 (1996).
Drescher, U., Bonhoeffer, F. & Muller, B. K. The Eph family in retinal axon guidance. Curr. Opin. Neurobiol. 7, 75–80 (1997).
Scarlatti, G.et al. In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Nature Med. 3, 1259–1265 (1997).
Connor, R. I., Sheridan, K. E., Ceradini, D., Choe, S. & Landau, N. R. Change in coreceptor use correlates with disease progression in HIV-1-infected individuals. J. Exp. Med. 185, 621–628 (1997).
Donzella, G. A.et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nature Med. 4, 72–77 (1998).
Gu, H., Zou, Y.-R. & Rajewsky, K. Independent control of immunogobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell 73, 1155–1164 (1993).
Schaeren-Wiemers, N. & Gerfin-Moser, A. Asingle protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 100, 431–440 (1993).
Landreth, K. S. & Dorshkind, K. Pre-B cell generation potentiated by soluble factors from a bone marrow stromal cell line. J. Immunol. 140, 845–852 (1988).
We thank F. Hatan and M.-J. Sunshine for technical assistance; S. Vukmanovic for help with the thymic transplant experiments; J. Johnson and N. Heitz for anti-Math1 and anti-BLBP antibodies; K. Dorshkind and R. R. Hardy for the S17 cell line; and G. Fishell, A. Joyner, M. Chao, C.Mason, S. Jung, V. KewalRamani and C. Davis for comments on the manuscript; Y.-R.Z. thanks H. Gu for his continuous support. This work was supported by an NIH grant (to D.R.L.). Y.-R.Z. is the recipient of a postdoctoral fellowship from the Irvington Institute, D.R.L. is an Investigator of the Howard Hughes Medical Institute.
About this article
Cite this article
Zou, YR., Kottmann, A., Kuroda, M. et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393, 595–599 (1998). https://doi.org/10.1038/31269
IEEE Access (2021)
The CXCL12gamma chemokine immobilized by heparan sulfate on stromal niche cells controls adhesion and mediates drug resistance in multiple myeloma
Journal of Hematology & Oncology (2021)
The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting
Annual Review of Pharmacology and Toxicology (2021)
Journal of Clinical Investigation (2021)
Proceedings of the National Academy of Sciences (2021)