Analysis of molecular mechanisms of development of mammalian eyes, brain, kidney and heart regulated by tyrosine kinases

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1. Analysis of molecular mechanisms of development through FRS2alpha-Shp2 pathway. We show that the carotid body is absent in FRS2alpha2F/2F mice and that the carotid body rudiment is not formed in the wall of the third arch artery in mutant embryos. We propose that the sympathetic ganglion provides glomus cell precursors into the third arch artery derivative.2. An FGF4-induced Cdx2-mediated BMP4 signaling pathway regulates a stem cell niche in mammalian embryos. We provide evidence that FGF4 derived from the ICM activates an FRS2alpha-ERK pathway resulting in enhanced expression of transcription factor Cdx2 in trophoblast stem cells. Cdx2 In turn binds to an FGF4-responsive enhancer element of the promoter region of Bmp4, leading to production and secretion of Bmp4.3. FRS2alpha mediates FGF signaling for the proliferation and self-renewal of neural stem/progenitor cells (NSPCs). Expression of wild type FRS2alpha promoted the proliferation of NSPCs in the presence of FGF2 but not EGF. The knockdown of FRS2alpha resulted in a reduction in proliferation of NSPCs. We demonstrate that FGF2-induced tyrosine phosphorylation of FRS2alpha is important not only for the proliferation but also for the self-renewal of NSPCs and raise a possibility of manipulating FRS2alpha in NSPCs for cell replacement therapy.