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Prepublished online as a Blood First Edition Paper on June 5, 2003; DOI 10.1182/blood-2003-04-1171. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-04-1171v1 102/6/2074    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chan, R. J. Articles by Feng, G.-S. Search for Related Content PubMed PubMed Citation Articles by Chan, R. J. Articles by Feng, G.-S. Related Collections Hematopoiesis and Stem Cells Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 September 2003, Vol. 102, No. 6, pp. 2074-2080 HEMATOPOIESIS A definitive role of Shp-2 tyrosine phosphatase in mediating embryonic stem cell differentiation and hematopoiesis Rebecca J. Chan, Scott A. Johnson, Yanjun Li, Mervin C. Yoder, and Gen-Sheng Feng From the Departments of Pediatrics and of Biochemistry and Molecular Biology, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis; and Program in Signal Transduction Research, The Burnham Institute, La Jolla, CA. Homozygous mutant (Shp-246-110) embryonic stem (ES) cells exhibit decreased hematopoiesis; however, the point at which Shp-2 is critical for ES cell differentiation to hematopoietic cells is unknown. We characterized the differentiation defect of Shp-246-110 ES cells by examining early points of differentiation, conducting leukemia inhibitory factor (LIF)–stimulated biochemical analysis, and performing in vitro reconstitution studies with wild-type (WT) Shp-2. ES cell in vitro differentiation assays were used to compare the differentiation of WT, Shp-246-110, and reconstituted ES cells to mesoderm, by measuring brachyury expression, to hemangioblasts, by measuring blast colony-forming cell (BL-CFC) formation and flk-1 expression, and to hematopoietic progenitor colony-forming cells, by performing secondary plating assays. LIF-stimulated phospho-Stat3 (known to be critical for ES cell self-renewal and maintenance of an undifferentiated state) and phospho-Erk levels were examined by immunoblotting. ES cell survival, using annexin V staining, and secondary embryoid body (EB) formation were also evaluated. Differentiation to both mesoderm and hemangioblasts was lower in Shp-246-110 cells compared to WT cells. On reconstitution with WT Shp-2, expression of brachyury and flk-1 and differentiation to hemangioblasts and primitive and definitive hematopoietic progenitors were restored. LIF-stimulated phospho-Stat3 levels were higher, whereas phospho-Erk levels were lower in Shp-246-110 ES cells than in WT and reconstituted cells. The increased phospho-Stat3 levels correlated with increased Shp-246-110 ES cell secondary EB formation and survival. We conclude that normal Shp-2 function is critical for the initial step of ES cell differentiation to mesoderm and to hemangioblasts and acts within the LIF-gp130-Stat3 pathway to maintain a proper balance of ES cell differentiation, pluripotency, and apoptosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Ke, E. E. Zhang, K. Hagihara, D. Wu, Y. Pang, R. 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