| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2002: ¥2,900,000 (Direct Cost: ¥2,900,000)
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| Research Abstract |
The docking protein FRS2α is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2α in vivo remains unknown. We show that Frs2α-null mouse embryos have a defect in anterior-posterior (A-P) axis formation, and are developmentally retarded resulting in embryonic lethality by E8.0. We demonstrate that FRS2α 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 FRS2α 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 MAP kinase dependent FGF4 stimulation. Moreover, both the expression of Bmp4 in ExE and activation of Smadl/5 in epiblasts are reduced in FRS2α-null embryos. These experiments underscore the critical role of FRS2α. in mediating
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multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis.
Early development of the lens and retina is dependent upon reciprocal inductive interactions between the embryonic surface ectoderm and the underlying neuroepithelium of the optic vesicle. FGF signaling has been implicated in this signal exchange. We explore the role of signaling pathways downstream of FRS2α in eye development by analyzing the phenotypes of mice that carry point mutations in either the Grb2 binding sites (Frs2α^<4F>) or the Shp2 binding sites (Frs2α^<2F>)of FRS2α. While FRS2α^<4F/4F> mice exhibited normal early eye development, all Frs2α^<2F/2F> embryos were defective in eye development and showed anophthalmia or microphthalmia. Consistent with the critical role of FRS2α in FGF signaling, the level of activated ERK in Frs2α^<2F/2F> embryos was significantly lower than that observed in wild type embryos. Furthermore, expression of Pax6 and Six3, molecular markers tor lens induction, were decreased in the Frs2α^<2F/2F> presumptive lens ectoderm. Similarly, the expression of ChxlO and Bmp4; genes required for retinal precursor proliferation and for lens development, respectively, was also decreased in the optic vesicles of FRS2α^<2F/2F> mice. These experiments demonstrate that specific tyrosine residues in FRS2α play an important role in eye development and suggest that an FGFR-FRS2α-Shp2-MAPK signaling pathway lies upstream of gene products critical for induction of lens and retina. Less
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