Abstract
The docking protein FRS2alpha is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2alpha in vivo remains unknown. In this report, we show that Frs2alpha-null mouse embryos have a defect in anterior-posterior (A-P) axis formation and are developmentally retarded, resulting in embryonic lethality by embryonic day 8. We demonstrate that FRS2alpha is essential for the maintenance of self-renewing trophoblast stem (TS) cells in response to FGF4 in the extraembryonic ectoderm (ExE) that gives rise to tissues of the placenta. By analyzing chimeric embryos, we found that FRS2alpha also plays a role in cell movement through the primitive streak during gastrulation. In addition, experiments are presented demonstrating that Bmp4 expression in TS cells is controlled by mitogen-activated protein kinase-dependent FGF4 stimulation. Moreover, both the expression of Bmp4 in ExE and activation of Smad1/5 in epiblasts are reduced in Frs2alpha-null embryos. These experiments underscore the critical role of FRS2alpha in mediating multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Body Patterning
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Bone Morphogenetic Protein 4
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Bone Morphogenetic Proteins / deficiency
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Bone Morphogenetic Proteins / genetics
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Cell Movement
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Cell Survival
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Chimera / abnormalities
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Chimera / embryology
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Chimera / genetics
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian / cytology
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Embryo, Mammalian / drug effects*
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Embryo, Mammalian / embryology
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Embryo, Mammalian / metabolism
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblast Growth Factor 4
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Fibroblast Growth Factors / pharmacology*
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Gastrula / drug effects
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Gastrula / pathology
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Gene Deletion
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Gene Expression Regulation, Developmental / drug effects
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Nodal Protein
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins / pharmacology*
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Signal Transduction / drug effects*
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Smad Proteins
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Smad1 Protein
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Trans-Activators / metabolism
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Transforming Growth Factor beta / deficiency
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Transforming Growth Factor beta / genetics
Substances
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Bmp4 protein, mouse
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Bone Morphogenetic Protein 4
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Bone Morphogenetic Proteins
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DNA-Binding Proteins
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FRS2alpha protein, mouse
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Fgf4 protein, mouse
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Fibroblast Growth Factor 4
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Membrane Proteins
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Nodal Protein
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Nodal protein, mouse
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Proto-Oncogene Proteins
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Smad Proteins
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Smad1 Protein
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Smad1 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta
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Fibroblast Growth Factors
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Extracellular Signal-Regulated MAP Kinases