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The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract


Vascularization of organs generally occurs by remodelling of the preexisting vascular system during their differentiation and growth to enable them to perform their specific functions during development. The molecules required by early vascular systems, many of which are receptor tyrosine kinases and their ligands, have been defined by analysis of mutant mice1,2,3. As most of these mice die during early gestation before many of their organs have developed, the molecules responsible for vascularization during organogenesis have not been identified. The cell-surface receptor CXCR4 (46) is a seven-transmembrane-spanning, G-protein-coupled receptor for the CXC chemokine PBSF/SDF-1 (for pre-B-cell growth-stimulating factor/stromal-cell-derived factor), which is responsible for B-cell lymphopoiesis, bone-marrow myelopoiesis and cardiac ventricular septum formation7. CXCR4 also functions as a co-receptor for T-cell-line tropic human immunodeficiency virus HIV-1 (ref. 8). Here we report that CXCR4 is expressed in developing vascular endothelial cells, and that mice lacking CXCR4 or PBSF/SDF-1 have defective formation of the large vessels supplying the gastrointestinal tract. In addition, mice lacking CXCR4 die in utero and are defective in vascular development, haematopoiesis and cardiogenesis, like mice lacking PBSF/SDF-1, indicating that CXCR4 is a primary physiological receptor for PBSF/SDF-1. We conclude that PBSF/SDF-1 and CXCR4 define a new signalling system for organ vascularization.

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Figure 1: Targeted disruption of the CXCR4 gene.
Figure 2: Formation of large vessels supplying intestines in embryonic mice.
Figure 3: Vasculature of the stomach of embryonic mice.
Figure 4: Vascular defects in the gastrointestinal tract of PBSF/SDF-1−/− embryos.
Figure 5: In situ hybridization analysis of CXCR4 and PBSF/SDF-1 expression in the gastroientestinal tract.
Figure 6: Defects of haematopoiesis and cardiogenesis in CXCR4−/− mice.


  1. 1

    Risau, W. Mechanisms of angiogenesis. Nature 386, 671–674 (1997).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Folkman, J. & D'Amore, P. A. Blood vessel formation: what is its molecular basis? Cell 87, 1153–1155 (1996).

    CAS  Article  Google Scholar 

  3. 3

    Lindahl, P., Johansson, B. R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997).

    CAS  Article  Google Scholar 

  4. 4

    Bleul, C. al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833 (1996).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Oberlin, 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).

    ADS  CAS  Article  Google Scholar 

  6. 6

    Nagasawa, al. Molecular cloning and characterization of a murine pre-B-cell growth-stimualting factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin. Proc. Natl Acad. Sci. USA 93, 14726–14729 (1996).

    ADS  CAS  Article  Google Scholar 

  7. 7

    Nagasawa, al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Feng, Y., Broder, C. C., Kennedy, P. E. & Berger, E. A. HIV-1 entry corecptor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872–877 (1996).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Baggiolini, M., Dewald, B. & Moser, B. Human chemokines: an update. Annu. Rev. Immunol. 15, 675–705 (1997).

    CAS  Article  Google Scholar 

  10. 10

    Vecchi, al. Monoclonal antibodies specific for endothelial cells of mouse blood vessels. Their application in the identification of adult and embryonic endothelium. Eur. J. Cell Biol. 63, 247–255 (1994).

    CAS  PubMed  Google Scholar 

  11. 11

    Baldwin, H. al. Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31): alternatively spliced, functionally distinct isoforms expressed during mammalian cardiovascular development. Development 120, 2539–2553 (1994).

    CAS  PubMed  Google Scholar 

  12. 12

    Shalaby, al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nautre 376, 62–66 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Fong, G.-H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70 (1995).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Dumont, D. al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 8, 1897–1909 (1994).

    CAS  Article  Google Scholar 

  15. 15

    Sato, T. al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74 (1995).

    ADS  CAS  Article  Google Scholar 

  16. 16

    Carmeliet, al. Abnormal blood vessel development and lethality in embryos lacking a single vEGF allele. Nature 380, 435–439 (1996).

    ADS  CAS  Article  Google Scholar 

  17. 17

    Ferrara, al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).

    ADS  CAS  Article  Google Scholar 

  18. 18

    Suri, al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171–1180 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Maione, T. al. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 247, 77–79 (1990).

    ADS  CAS  Article  Google Scholar 

  20. 20

    Koch, A. al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258, 1798–1801 (1992).

    ADS  CAS  Article  Google Scholar 

  21. 21

    Luster, A. D., Greenberg, S. M. & Leder, P. The IP-10 chemokine bind to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J. Exp. Med. 182, 219–231 (1995).

    CAS  Article  Google Scholar 

  22. 22

    Cao, Y., Chen, C., Weatherbee, J. A., Tsang, M. & Folkman, J. gro-β, a CXC chemokine, is an angiogenesis inhibitor that suppresses the growth of Lewis lung carcinoma in mice. J. Exp. Med. 182, 2069–2077 (1995).

    CAS  Article  Google Scholar 

  23. 23

    Cui, J., Sue O'Shea,, Purkayastha, A., Saunders, T. L. & Ginsburg, D. Fatal haemorrhage and incomplete block ot embryogenesis in mice lacking coagulation factor V. Nature 384, 66–68 (1996).

    ADS  CAS  Article  Google Scholar 

  24. 24

    Carmeliet, al. Role of tissue factor in embryonic blood vessel development. Nature 383, 73–75 (1996).

    ADS  CAS  Article  Google Scholar 

  25. 25

    Offermanns, S., Mancino, V., Revel, J.-P. & Simon, M. I. Vascular system defects and impaired cell chemokinesis as a result of Gα13deficiency. Science 275, 533–535 (1997).

    CAS  Article  Google Scholar 

  26. 26

    Fauci, A. S. Host factors and the pathogenesis of HIV-induced disease. Nature 384, 529–535 (1996).

    ADS  CAS  Article  Google Scholar 

  27. 27

    Liu, al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Samson, al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the R-5 chemokine receptor gene. Nature 382, 722–725 (1996).

    ADS  CAS  Article  Google Scholar 

  29. 29

    Dean, al. Genetic restriction of HIV-1 infection and progression to AIDS by a detection allele of the CCR5 structural gene. Science 273, 1856–1861 (1996).

    ADS  CAS  Article  Google Scholar 

  30. 30

    Adachi, S., Yoshida, H., Kataoka, H. & Nishikawa, S.-I. Three distinctive steps in Peyer's patch formation of murine embryo. Int. Immunol. 9, 507–514 (1997).

    CAS  Article  Google Scholar 

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We thank K. Morihana, T. Ohito and T. Iwaki for technical assistance; T. Tanaka for technical advice; and T. Nakajima for discussion. This work was supported by grants from the Ministry of Education of Japan.

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Correspondence to Takashi Nagasawa.

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Tachibana, K., Hirota, S., Iizasa, H. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393, 591–594 (1998).

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