XB-ART-36582Development. November 1, 2007; 134 (22): 4119-30.
SHP-2 is required for the maintenance of cardiac progenitors.
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.
PubMed ID: 17928416
PMC ID: PMC2807747
Article link: Development.
Grant support: 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 , P30-S045892-02 PHS HHS , R01 HL075256-04 NHLBI NIH HHS , R01 HL075256 NHLBI NIH HHS , R21 HL083965-02 NHLBI NIH HHS , HL075256-01S1 NHLBI NIH HHS , K12 GM000678 NIGMS NIH HHS , GM 00678 NIGMS NIH HHS , R21 HL083965 NHLBI NIH HHS
Genes referenced: a2m aplnr cfd darmin fgf8 mapk1 myh4 myh6 nkx2-5 nr0b2 ptpn11 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.|
|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.|