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Prepublished online as a Blood First Edition Paper on September 19, 2002; DOI 10.1182/blood-2002-02-0655.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 886-893
HEMATOPOIESIS
Hemogenic and nonhemogenic 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
From the Department of Microbiology, Kyoto Prefectural
University of Medicine, Kyoto, Japan; Department of Molecular Genetics,
Faculty of Medicine, Kyoto University, Kyoto, Japan; Center for Tsukuba
Advanced Research Alliance and Institute of Basic Medical Sciences,
University of Tsukuba, Tsukuba, Japan; Max-Planck-Institute for
Physiological and Clinical Research, Bad Nauheim, Germany.
Accumulating evidence in various species has suggested that the
origin of definitive hematopoiesis is associated with a special subset
of endothelial cells (ECs) that maintain the potential to give rise to
hematopoietic cells (HPCs). 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 by 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 vascular endothelial
(VE)-cadherin+ ECs. Emergence of GFP ECs
preceded that of GFP+ ECs, and, finally, most ECs expressed
GFP both in vitro and in vivo. Cell sorting experiments demonstrated
that only GFP ECs could give rise to HPCs and
preferentially expressed Runx1 and c-Myb genes
that are required for the definitive hematopoiesis. Integration of both
GFP+ and GFP ECs was observed in the dorsal
aorta, but cell clusters appeared associated only to GFP
ECs. 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 endothelial and hematopoietic lineages.
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