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

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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 (6,​ 7,​ 8,​ 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.