The Journal of Experimental Medicine
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Published online 23 February 2004 doi:10.1084/jem.20030830
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 5, 737-742
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Brief Definitive Report

 Spred-2 Suppresses Aorta-Gonad-Mesonephros Hematopoiesis by Inhibiting MAP Kinase Activation

Ikuo Nobuhisa1, Reiko Kato2, Hirofumi Inoue1, Makiko Takizawa1, Keisuke Okita1, Akihiko Yoshimura2, and Tetsuya Taga1

1 Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
2 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

Address correspondence to Tetsuya Taga, Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1, Honjo, Kumamoto 860-0811, Japan. Phone: 81-96-373-6610; Fax: 81-96-373-6610; email: taga{at}kaiju.medic.kumamoto-u.ac.jp

In midgestation mouse embryos, the aorta-gonad-mesonephros (AGM) region generates hematopoietic stem cells and definitive hematopoiesis is regulated by cell–cell interaction and signaling molecules. We showed that a Ras/mitogen-activated protein (MAP) kinase signaling-specific inhibitor and a dominant negative mutant Ras blocked the production of CD45+ hematopoietic cells in embryonic day 11.5 AGM culture, indicating an essential role for the MAP kinase pathway in AGM hematopoiesis. Overexpression of the Ras/MAP kinase pathway regulator, Spred-2, in the AGM culture significantly reduced the number of CD45+ cells. In contrast, production of CD45+ cells from the AGM region of Spred-2–null mice was up-regulated as compared with wild-type littermates. Furthermore, Spred-2–deficient mice exhibited elevated hematopoietic colony formation from vascular endothelial-cadherin+ cells. These data indicate that Spred-2 functions as a negative regulator of AGM hematopoiesis by inhibiting hematopoietic cytokine signaling.

Key Words: hematopoiesis • differentiation • SCF • c-Kit • AGM

The online version of this article contains supplemental material.


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