XB-ART-36582
Development
2007 Nov 01;13422:4119-30. doi: 10.1242/dev.009290.
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SHP-2 is required for the maintenance of cardiac progenitors.
Langdon YG
,
Goetz SC
,
Berg AE
,
Swanik JT
,
Conlon FL
.
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The isolation and culturing of cardiac progenitor cells has demonstrated that growth factor signaling is required to maintain cardiac cell survival and proliferation. In this study, we demonstrate in Xenopus that SHP-2 activity is required for the maintenance of cardiac precursors in vivo. In the absence of SHP-2 signaling, cardiac progenitor cells downregulate genes associated with early heart development and fail to initiate cardiac differentiation. We further show that this requirement for SHP-2 is restricted to cardiac precursor cells undergoing active proliferation. By demonstrating that SHP-2 is phosphorylated on Y542/Y580 and that it binds to FRS-2, we place SHP-2 in the FGF pathway during early embryonic heart development. Furthermore, we demonstrate that inhibition of FGF signaling mimics the cellular and biochemical effects of SHP-2 inhibition and that these effects can be rescued by constitutively active/Noonan-syndrome-associated forms of SHP-2. Collectively, these results show that SHP-2 functions within the FGF/MAPK pathway to maintain survival of proliferating populations of cardiac progenitor cells.
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???displayArticle.grants??? [+]
GM 00678 NIGMS NIH HHS , HL075256-01S1 NHLBI NIH HHS , P30-S045892-02 PHS HHS , R01 HL075256 NHLBI NIH HHS , R21 HL083965 NHLBI NIH HHS , R01 HL075256-04 NHLBI NIH HHS , R21 HL083965-02 NHLBI NIH HHS , K12 GM000678 NIGMS NIH HHS
Species referenced: Xenopus laevis
Genes referenced: a2m aplnr cfd darmin fgf8 mapk1 myh4 myh6 nkx2-5 nr0b2 ptpn11 ptpn11b sox2 tbx1 tbx20 tbx5 tpm1
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Fig. 1. Inhibition of SHP-2 activity results in loss of MHC expression. Tissue explants show identical cardiac expression profiles as intact Xenopus embryos. (A) Whole-mount antibody staining of cardiac differentiation with tropomyosin (Tmy; red) or myosin heavy chain (MHC; red) antibodies as indicated, in whole embryos and cardiac explants at stages 22 (neurula), 29 (tailbud) and 37 (tadpole). (B) Whole-mount in situ hybridization for early heart markers Tbx5, Tbx20, Nkx2.5 in whole embryos and cardiac explants at stage 22, 29 and 37, as indicated. (C) MHC expression is dependent on SHP-2 activity. Whole-mount antibody staining for MHC (red) in cardiac explants taken from uninjected (control) embryos or embryos injected with Shp-2 N308D and treated with either buffer or DMSO carrier as controls or with NSC-87877 as indicated. BF, bright field. |
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Fig. 3. SHP-2 activity is required for pharyngeal mesoderm. (A) Schematic of tissues and rudimentary organ structures in Xenopus tissue explants. (B) Cardiac explants isolated and cultured in DMSO or NSC-87877 (NSC) beginning at stage 22. In situ hybridization performed on explants with Tbx1, Fgf8, at stages 22, 26, 29 and 33. (C) Whole-mount in situ hybridization of Endocut, Endodermin, Sox2, Ami and Xmsr at stage 37; whole embryos and cardiac explants treated with DMSO (control) or NSC-87877, as indicated. |
References [+] :
Alexander,
casanova plays an early and essential role in endoderm formation in zebrafish.
1999, Pubmed,
Xenbase
Alexander, casanova plays an early and essential role in endoderm formation in zebrafish. 1999, Pubmed , Xenbase
Alexiades, Quantitative analysis of proliferation and cell cycle length during development of the rat retina. 1996, Pubmed
Allanson, The first Noonan syndrome gene: PTPN11, which encodes the protein tyrosine phosphatase SHP-2. 2002, Pubmed
Alsan, Regulation of avian cardiogenesis by Fgf8 signaling. 2002, Pubmed , Xenbase
Araki, Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. 2004, Pubmed
Bjørbaek, Divergent roles of SHP-2 in ERK activation by leptin receptors. 2001, Pubmed
Brown, Small heat shock protein Hsp27 is required for proper heart tube formation. 2007, Pubmed , Xenbase
Brown, Developmental expression of the Xenopus laevis Tbx20 orthologue. 2003, Pubmed , Xenbase
Brown, Tbx5 and Tbx20 act synergistically to control vertebrate heart morphogenesis. 2005, Pubmed , Xenbase
Bruneau, A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. 2001, Pubmed
Cai, T-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis. 2005, Pubmed
Chan, Shp-2 heterozygous hematopoietic stem cells have deficient repopulating ability due to diminished self-renewal. 2006, Pubmed
Chen, Discovery of a novel shp2 protein tyrosine phosphatase inhibitor. 2006, Pubmed
Christofori, Split personalities: the agonistic antagonist Sprouty. 2003, Pubmed
Costa, Novel gene expression domains reveal early patterning of the Xenopus endoderm. 2003, Pubmed , Xenbase
DEHAAN, Migration patterns of the precardiac mesoderm in the early chick embrvo. 1963, Pubmed
Dale, Fate map for the 32-cell stage of Xenopus laevis. 1987, Pubmed , Xenbase
Dasso, Completion of DNA replication is monitored by a feedback system that controls the initiation of mitosis in vitro: studies in Xenopus. 1990, Pubmed , Xenbase
Delahaye, Potential involvement of FRS2 in insulin signaling. 2000, Pubmed
Dyer, Regulating proliferation during retinal development. 2001, Pubmed
Feng, Shp-2 tyrosine phosphatase: signaling one cell or many. 1999, Pubmed
Fishman, Fashioning the vertebrate heart: earliest embryonic decisions. 1997, Pubmed
Georgescu, Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. 2000, Pubmed
Goetz, TBX5 is required for embryonic cardiac cell cycle progression. 2006, Pubmed , Xenbase
Goetz, Cardiac progenitors and the embryonic cell cycle. 2007, Pubmed
Gove, Over-expression of GATA-6 in Xenopus embryos blocks differentiation of heart precursors. 1997, Pubmed , Xenbase
Grossel, From cell cycle to differentiation: an expanding role for cdk6. 2006, Pubmed
Guillemot, The protein-tyrosine phosphatase SHP-2 is required during angiotensin II-mediated activation of cyclin D1 promoter in CHO-AT1A cells. 2000, Pubmed
Hanafusa, Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty. 2004, Pubmed
Harland, In situ hybridization: an improved whole-mount method for Xenopus embryos. 1991, Pubmed , Xenbase
Harris, Neuronal determination without cell division in Xenopus embryos. 1991, Pubmed , Xenbase
Harvey, Homeodomain factor Nkx2-5 in heart development and disease. 2002, Pubmed , Xenbase
Hensey, Programmed cell death during Xenopus development: a spatio-temporal analysis. 1998, Pubmed , Xenbase
Horb, Tbx5 is essential for heart development. 1999, Pubmed , Xenbase
House, Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade. 2005, Pubmed
Huebert, Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart. 2004, Pubmed
Ilagan, Fgf8 is required for anterior heart field development. 2006, Pubmed
Inui, A novel gene, Ami is expressed in vascular tissue in Xenopus laevis. 2006, Pubmed , Xenbase
Jarvis, Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases. 2006, Pubmed
Jiang, Acute protection of ischemic heart by FGF-2: involvement of FGF-2 receptors and protein kinase C. 2002, Pubmed
Jiang, Non-angiogenic FGF-2 protects the ischemic heart from injury, in the presence or absence of reperfusion. 2004, Pubmed
Jiang, The Xenopus GATA-4/5/6 genes are associated with cardiac specification and can regulate cardiac-specific transcription during embryogenesis. 1996, Pubmed , Xenbase
Kattman, Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. 2006, Pubmed
Kim, Modulation of signalling by Sprouty: a developing story. 2004, Pubmed
Kolker, Confocal imaging of early heart development in Xenopus laevis. 2000, Pubmed , Xenbase
Kouhara, A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. 1997, Pubmed
Kouskoff, Sequential development of hematopoietic and cardiac mesoderm during embryonic stem cell differentiation. 2005, Pubmed
Kupperman, A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development. 2000, Pubmed
Lathrop, Control of myogenic differentiation by fibroblast growth factor is mediated by position in the G1 phase of the cell cycle. 1985, Pubmed
Li, Pan-neural Prospero terminates cell proliferation during Drosophila neurogenesis. 2000, Pubmed
Lu, PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. 2004, Pubmed , Xenbase
Lyons, Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. 1995, Pubmed
Maheshwari, PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. 2002, Pubmed
Mason, Modulation of Kv1.5 currents by protein kinase A, tyrosine kinase, and protein tyrosine phosphatase requires an intact cytoskeleton. 2002, Pubmed , Xenbase
Mills, Elucidating the origins of the vascular system: a fate map of the vascular endothelial and red blood cell lineages in Xenopus laevis. 1999, Pubmed , Xenbase
Molkentin, Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. 1997, Pubmed
Moody, Fates of the blastomeres of the 32-cell-stage Xenopus embryo. 1987, Pubmed , Xenbase
Moretti, Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. 2006, Pubmed
Nguyen, Coupling cell cycle exit, neuronal differentiation and migration in cortical neurogenesis. 2006, Pubmed
Noonan, Noonan syndrome: a clinical description emphasizing the cardiac findings. 1996, Pubmed
Palmen, Fibroblast growth factor-1 improves cardiac functional recovery and enhances cell survival after ischemia and reperfusion: a fibroblast growth factor receptor, protein kinase C, and tyrosine kinase-dependent mechanism. 2004, Pubmed
Parmacek, Pursuing cardiac progenitors: regeneration redux. 2005, Pubmed
Pasumarthi, Cardiomyocyte cell cycle regulation. 2002, Pubmed
Pawson, Tyrosine kinase signalling pathways. 1994, Pubmed
Qu, The SHP-2 tyrosine phosphatase: signaling mechanisms and biological functions. 2000, Pubmed
Raffin, Subdivision of the cardiac Nkx2.5 expression domain into myogenic and nonmyogenic compartments. 2000, Pubmed , Xenbase
Reiter, Gata5 is required for the development of the heart and endoderm in zebrafish. 1999, Pubmed , Xenbase
Saga, MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. 1999, Pubmed
Sater, The specification of heart mesoderm occurs during gastrulation in Xenopus laevis. 1989, Pubmed , Xenbase
Schollen, PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning. 2003, Pubmed
Singh, Tbx20 is essential for cardiac chamber differentiation and repression of Tbx2. 2005, Pubmed
Smith, Dorsalization and neural induction: properties of the organizer in Xenopus laevis. 1983, Pubmed , Xenbase
Srivastava, Making or breaking the heart: from lineage determination to morphogenesis. 2006, Pubmed
Stennard, Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation. 2005, Pubmed
Takeuchi, Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development. 2005, Pubmed
Tang, The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. 1995, Pubmed , Xenbase
Tartaglia, Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. 2001, Pubmed
Tartaglia, PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. 2002, Pubmed
Tonissen, XNkx-2.5, a Xenopus gene related to Nkx-2.5 and tinman: evidence for a conserved role in cardiac development. 1994, Pubmed , Xenbase
Trinh, Fibronectin regulates epithelial organization during myocardial migration in zebrafish. 2004, Pubmed
Tsang, Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. 2004, Pubmed , Xenbase
Van Vactor, Genetic analysis of protein tyrosine phosphatases. 1998, Pubmed
Vernon, A single cdk inhibitor, p27Xic1, functions beyond cell cycle regulation to promote muscle differentiation in Xenopus. 2003, Pubmed , Xenbase
Walsh, Cell cycle exit upon myogenic differentiation. 1997, Pubmed
Warkman, Xenopus as a model system for vertebrate heart development. 2007, Pubmed , Xenbase
Wu, Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. 2006, Pubmed , Xenbase
Yang, An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. 2006, Pubmed
Yuan, SHP-2 phosphatase regulates DNA damage-induced apoptosis and G2/M arrest in catalytically dependent and independent manners, respectively. 2005, Pubmed
Yuan, DNA damage-induced G2/M checkpoint in SV40 large T antigen-immortalized embryonic fibroblast cells requires SHP-2 tyrosine phosphatase. 2003, Pubmed
Zhang, Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling. 2000, Pubmed
van den Hoff, Making more heart muscle. 2004, Pubmed