Negative Feedback Regulation of FGF Signaling Levels by Pyst1/MKP3 in Chick Embryos

Background: The importance of endogenous antagonists in intracellular signal transduction pathways is becoming increasingly recognized. There is evidence in cultured mammalian cells that Pyst1/MKP3, a dual specificity protein phosphatase, specifically binds to and inactivates ERK1/2 mitogen-activate...

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Published in:	Current biology Vol. 13; no. 12; pp. 1009 - 1018
Main Authors:	Eblaghie, Maxwell C., Lunn, J.Simon, Dickinson, Robin J., Münsterberg, Andrea E., Sanz-Ezquerro, Juan-Jose, Farrell, Elizabeth R., Mathers, Joanne, Keyse, Stephen M., Storey, Kate, Tickle, Cheryll
Format:	Journal Article
Language:	English
Published:	England Elsevier Inc 17-06-2003
Subjects:	Animals Blotting, Western Chick Embryo DNA Primers Dual Specificity Phosphatase 6 Electroporation Feedback, Physiological Fibroblast Growth Factors - antagonists & inhibitors Fibroblast Growth Factors - metabolism Gene Expression Regulation, Developmental Heparin Immunohistochemistry In Situ Hybridization Limb Buds MAP Kinase Signaling System - physiology Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors Protein Tyrosine Phosphatases - metabolism Pyrroles - metabolism Signal Transduction - physiology
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Summary:	Background: The importance of endogenous antagonists in intracellular signal transduction pathways is becoming increasingly recognized. There is evidence in cultured mammalian cells that Pyst1/MKP3, a dual specificity protein phosphatase, specifically binds to and inactivates ERK1/2 mitogen-activated protein kinases (MAPKs). High-level Pyst1/Mkp3 expression has recently been found at many sites of known FGF signaling in mouse embryos, but the significance of this association and its function are not known. Results: We have cloned chicken Pyst1/Mkp3 and show that high-level expression in neural plate correlates with active MAPK. We show that FGF signaling regulates Pyst1 expression in developing neural plate and limb bud by ablating and/or transplanting tissue sources of FGFs and by applying FGF protein or a specific FGFR inhibitor (SU5402). We further show by applying a specific MAP kinase kinase inhibitor (PD184352) that Pyst1 expression is regulated via the MAPK cascade. Overexpression of Pyst1 in chick embryos reduces levels of activated MAPK in neural plate and alters its morphology and retards limb bud outgrowth. Conclusions: Pyst1 is an inducible antagonist of FGF signaling in embryos and acts in a negative feedback loop to regulate the activity of MAPK. Our results demonstrate both the importance of MAPK signaling in neural induction and limb bud outgrowth and the critical role played by dual specificity MAP kinase phosphatases in regulating developmental outcomes in vertebrates.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0960-9822 1879-0445
DOI:	10.1016/S0960-9822(03)00381-6