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Prepublished online as a Blood First Edition Paper on September 19, 2002; DOI 10.1182/blood-2002-02-0655.
Submitted February 28, 2002
Accepted September 9, 2002
Hemogenic and non-hemogenic endothelium can be distinguished by the activity of fetal liver kinase (Flk)-1 promoter/enhancer during mouse embryogenesis
Hideyo Hirai*, Minetaro Ogawa, Norio Suzuki, Masayuki Yamamoto, Georg Breier, Osam Mazda, Jiro Imanishi, and Shin-Ichi Nishikawa
Department of Microbiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Department of Molecular Genetics, Kyoto University, Faculty of Medicine, Kyoto, Japan
Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Science, University of Tsukuba, Tsukuba, Japan
Max Planck Insititute for Physiological and Clinical Research, Bad Nauheim, Germany
* Corresponding author; email: hhirai{at}basic.kpu-m.ac.jp.
Accumulating evidence in various species have suggested that the origin of definitive hematopoiesis is associated with a special subset of endothelial cells (EC) that maintain the potential to give rise to hematopoietic cells (HPC). In this study, we demonstrated that a combination of 5' flanking region and 3' portion of the first intron of the Flk-1 gene (Flk-1 p/e) that has been implicated in endothelium-specific gene expression distinguishes prospectively the EC that has lost hemogenic activity. We assessed the activity of this Flk-1 p/e by embryonic stem (ES) cell differentiation culture and transgenic mice using the GFP gene conjugated to this unit. The expression of GFP differed from that of the endogenous Flk-1 gene in that it is active in undifferentiated ES cells and inactive in Flk-1+ lateral mesoderm. Flk-1 p/e becomes active after generation of VE-cadherin+ EC. Emergence of GFP- EC preceded that of GFP+ EC and, finally, the majority of EC expressed GFP both in vitro and in vivo. Cell sorting experiments demonstrated that only GFP- EC could give rise to HPC and preferentially expressed Runx1 and c-Myb genes that are required for the definitive hematopoiesis. Integration of both GFP+ and GFP- EC were observed in the dorsal aorta, but clusters of HPC appeared associated only to GFP- EC. These results indicate that activation of Flk-1 p/e is associated with a process that excludes HPC potential from the EC differentiation pathway and will be useful for investigating molecular mechanisms underlying the divergence of EC and HPC lineages.
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