Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development

Chemokines and their receptors are important in cell migration during inflammation, in the establishment of functional lymphoid microenvironments, and in organogenesis. The chemokine receptor CXCR4 is broadly expressed in cells of both the immune and the central nervous systems, and can mediate migration of resting leukocytes and haematopoietic progenitors in response to its ligand, SDF-1 (refs 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 dementia. Here we show that mice lacking CXCR4 exhibit haematopoietic and cardiac defects identical to those of SDF-1-deficient mice, 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.

[1]  D. Larhammar,et al.  Embryonic expression of the mRNA for the rat homologue of the fusin/CXCR-4 HIV-1 co-receptor , 1997, Journal of Neuroimmunology.

[2]  E. Wolf,et al.  A Putative Chemokine Receptor, BLR1, Directs B Cell Migration to Defined Lymphoid Organs and Specific Anatomic Compartments of the Spleen , 1996, Cell.

[3]  S. Nishikawa,et al.  Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1 , 1996, Nature.

[4]  P. Murphy.  Chemokine receptors: structure, function and role in microbial pathogenesis. , 1996, Cytokine & growth factor reviews.

[5]  E. Fenyö,et al.  In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression , 1997, Nature Medicine.

[6]  Paul E. Kennedy,et al.  HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein-Coupled Receptor , 1996, Science.

[7]  Timothy A. Springer,et al.  Adhesion receptors of the immune system , 1990, Nature.

[8]  S. Nishikawa,et al.  Stepwise progression of B lineage differentiation supported by interleukin 7 and other stromal cell molecules , 1990, The Journal of experimental medicine.

[9]  Hao Wang,et al.  Netrin-1 Is Required for Commissural Axon Guidance in the Developing Vertebrate Nervous System , 1996, Cell.

[10]  Bernhard Moser,et al.  The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1 , 1996, Nature.

[11]  J. Moore,et al.  AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor , 1998, Nature Medicine.

[12]  T. Springer,et al.  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 , 1997, The Journal of experimental medicine.

[13]  R. Connor,et al.  Change in Coreceptor Use Correlates with Disease Progression in HIV-1–Infected Individuals , 1997, The Journal of experimental medicine.

[14]  M. Hatten,et al.  The role of migration in central nervous system neuronal development , 1993, Current Opinion in Neurobiology.

[15]  M. Hatten,et al.  Mechanisms of neural patterning and specification in the developing cerebellum. , 1995, Annual review of neuroscience.

[16]  R. Kageyama,et al.  A Mammalian 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(*) , 1995, The Journal of Biological Chemistry.

[17]  M. Baggiolini,et al.  Two murine homologues of the human chemokine receptor CXCR4 mediating stromal cell‐derived factor 1α activation of Gi2 are differentially expressed in vivo , 1997, European journal of immunology.

[18]  K. Rajewsky,et al.  Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting , 1993, Cell.

[19]  A. Bradley,et al.  Ulcerative colitis and adenocarcinoma of the colon in Gαi2-deficient mice , 1995, Nature Genetics.

[20]  R. Perlmutter,et al.  Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP‐ribosyltransferase. , 1990, The EMBO journal.

[21]  A. Cumano,et al.  Circulation of hematopoietic progenitors in the mouse embryo. , 1996, Immunity.

[22]  K. Dorshkind,et al.  Pre-B cell generation potentiated by soluble factors from a bone marrow stromal cell line. , 1988, Journal of immunology.

[23]  M. Hatten,et al.  Brain lipid-binding protein (BLBP): A novel signaling system in the developing mammalian CNS , 1994, Neuron.

[24]  T. Springer,et al.  A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1) , 1996, The Journal of experimental medicine.

[25]  F. Bonhoeffer,et al.  The Eph family in retinal axon guidance , 1997, Current Opinion in Neurobiology.

[26]  E. Butcher,et al.  Chemokines and the arrest of lymphocytes rolling under flow conditions. , 1998, Science.

[27]  J D Kemp,et al.  Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow , 1991, The Journal of experimental medicine.

[28]  J. Sodroski,et al.  The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry , 1996, Nature.