Spred-2 suppresses aorta-gonad-mesonephros hematopoiesis by inhibiting MAP kinase activation.
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.
Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1, Honjo, 860-0811, Japan.
Ikuo
I
Nobuhisa
Reiko
R
Kato
Hirofumi
H
Inoue
Makiko
M
Takizawa
Keisuke
K
Okita
Akihiko
A
Yoshimura
Tetsuya
T
Taga
D000818:Animals; D001011:Aorta / Q000196:embryology / Q000201:enzymology; D001483:Base Sequence; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D005865:Gestational Age; D006066:Gonads / Q000196:embryology / Q000201:enzymology; D006410:Hematopoiesis / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D008650:Mesonephros / Q000196:embryology / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011247:Pregnancy; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; D017931:DNA Primers; D012097:Repressor Proteins; C433764:Spred2 protein, mouse; D020928:Mitogen-Activated Protein Kinases