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

Abstract

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 (69). 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.

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Figure 1: Targeted disruption of the CXCR4 gene.
Figure 2: Impaired haematopoiesis and SDF-1-induced chemotaxis, but normal development of T cells, in CXCR4−/− mice.
Figure 3: Localization of CXCR4 mRNA in the wild-type developing brain as shown by in situ hybridization.
Figure 4: Abnormal migration of cerebellar EGL cells in CXCR4−/− embryos.

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Acknowledgements

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.

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Correspondence to Yong-Rui Zou.

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