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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-02-0398.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 124-133
HEMATOPOIESIS
Disruption of Smad5 gene leads to enhanced
proliferation of high-proliferative potential precursors during
embryonic hematopoiesis
Bing Liu,
Yanxun Sun,
Feizi Jiang,
Shuangxi Zhang,
Ying Wu,
Yu Lan,
Xiao Yang, and
Ning Mao
From the Department of Cell Biology, Institute of Basic
Medical Sciences, Genetic Laboratory of Development and Diseases,
Institute of Biotechnology, and Department of Hematology, Yan Jing
Hospital, Beijing, Peoples' Republic of China.
SMAD proteins are downstream signal transducers of the
transforming growth factor  (TGF-) superfamily, which serve as
pleiotropic regulators in embryonic and adult hematopoiesis. SMAD5,
initially considered to mediate bone morphogenetic proteins
(BMPs) signals, can also transduce the inhibitory signal of
TGF-1 on proliferation of hematopoietic progenitors derived
from human bone marrow. To define its specific role in regulation of
primitive multipotential progenitors during early embryonic
hematopoiesis, we examined Smad5 / yolk sacs at E9.0 to
9.5 and detected an elevated number of high-proliferative potential
colony-forming cells (HPP-CFCs) with enhanced replating potential. To
exclude the possible influence of microenvironmental deficit on
embryonic hematopoiesis in vivo, we performed in vitro embryonic stem
(ES) cell differentiation assay and investigated the HPP-CFCs in
particular. Smad5/ embryoid bodies (EBs) contained an
elevated number of blast colony-forming cells (BL-CFCs), the in vitro
equivalent of hemangioblast, in contrast to reduced proliferation of
primitive erythroid precursors (Ery/Ps) within the mutant EBs. More
importantly, profoundly increased frequency of HPP-CFCs, featured with
a gene-dosage effect, was detected within day 6 Smad5/
EBs compared with the wild type. In addition, Smad5/
HPP-CFCs displayed enhanced self-renewal capacity and decreased sensitivity to TGF-1 inhibition, suggesting a critical role of Smad5
in TGF-1 regulation of embryonic HPP-CFCs. Consistently, reverse
transcription-polymerase chain reaction analysis detected alterations
of the transcription factors including GATA-2 and AML1 as well as
cytokine receptors in Smad5/ HPP-CFC colonies.
Together, these data define an important function of SMAD5 in negative
regulation of high-proliferative potential precursors during
embryonic hematopoiesis.
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