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

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Abstract

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.

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Acknowledgements

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) doi:10.1038/31261

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