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Molecular and Cellular Biology, October 1998, p. 6075-6082, Vol. 18, No. 10
Departments of Biochemistry and Molecular
Biology,1
Pathology and Laboratory
Medicine,4 and
Microbiology and
Immunology5 and
Walther Oncology
Center,2 Indiana University School of
Medicine, Indianapolis, Indiana 46202-5254, and
Walther
Cancer Institute, Indianapolis, Indiana 462083
Received 12 May 1998/Returned for modification 16 June
1998/Accepted 16 July 1998
Shp-2 is a cytoplasmic tyrosine phosphatase that contains two Src
homology 2 (SH2) domains at the N terminus. Biochemical data suggests
that Shp-2 acts downstream of a variety of receptor and
cytoplasmic tyrosine kinases. A targeted deletion mutation in the
N-terminal SH2 (SH2-N) domain results in embryonic lethality of
homozygous mutant mice at midgestation. In vitro embryonic stem (ES)
cell differentiation assays suggest that Shp-2 might play an
important role in hematopoiesis. By aggregating homozygous mutant
(Shp-2
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Biased Suppression of Hematopoiesis and Multiple Developmental
Defects in Chimeric Mice Containing Shp-2 Mutant Cells
/
) ES cells and wild-type (WT) embryos,
we created Shp-2
/
-WT chimeric animals. We
report here an essential role of Shp-2 in the control of blood
cell development. Despite the widespread contribution of mutant cells
to various tissues, no Shp-2
/
progenitors for
erythroid or myeloid cells were detected in the fetal liver and bone
marrow of chimeric animals by using the in vitro CFU assay.
Furthermore, hematopoiesis was defective in
Shp-2
/
yolk sacs. In addition, the
Shp-2 mutation caused multiple developmental defects in
chimeric mice, characterized by short hind legs, aberrant limb
features, split lumbar vertebrae, abnormal rib patterning, and
pathological changes in the lungs, intestines, and skin. These results
demonstrate a functional involvement of Shp-2 in the
differentiation of multiple tissue-specific cells and in body
organization. More importantly, the requirement for Shp-2 is
more stringent in hematopoiesis than in other systems.
*
Corresponding author. Mailing address: Walther Oncology
Center, Indiana University School of Medicine, 1044 W. Walnut St. Room
302, Indianapolis, IN 46202-5254. Phone: (317) 274-7515. Fax: (317)
274-7592. E-mail: gfeng{at}iupui.edu.
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