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

酪氨酸激酶调控哺乳动物眼、脑、肾、心脏发育的分子机制分析

• 批准号: 18590258
• 负责人: GOTOH Noriko
• 金额: $ 2.7万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590258/
• 关键词: stem cells; neuron; neural crest; FGF; adaptor molecule; 胎盤; 細胞内シグナル伝達; 心奇形

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.

1. frs2α - shp2通路发育的分子机制分析。我们发现在FRS2alpha2F/2F小鼠中没有颈动脉体，并且在突变胚胎的第三弓动脉壁中没有形成颈动脉体雏形。我们认为交感神经节为第三弓动脉衍生物提供了血管小球细胞前体。fgf4诱导的cdx2介导的BMP4信号通路调节哺乳动物胚胎干细胞生态位。我们提供的证据表明，来自ICM的FGF4激活了FRS2alpha-ERK通路，导致滋养细胞干细胞中转录因子Cdx2的表达增强。Cdx2反过来与Bmp4启动子区域的fgf4响应增强元件结合，导致Bmp4.3的产生和分泌。FRS2alpha介导神经干细胞/祖细胞（NSPCs）增殖和自我更新的FGF信号传导。野生型FRS2alpha的表达促进了FGF2存在时NSPCs的增殖，而不是EGF存在时的增殖。FRS2alpha的下调导致NSPCs的增殖减少。我们证明，fgf2诱导的FRS2alpha酪氨酸磷酸化不仅对NSPCs的增殖很重要，而且对NSPCs的自我更新也很重要，并提出了在NSPCs中操纵FRS2alpha进行细胞替代治疗的可能性。

项目成果

Feedback inhibitors of the epidermal growth factor receptor signaling pathways

• DOI: 10.1016/j.biocel.2008.06.019
• 发表时间: 2009-03-01
• 期刊: INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
• 影响因子: 4
• 作者: Gotoh, Noriko

Unique role of SNT-2/FRS2β/FRS3 ducking/adaptor protein for negative regulation of EGF receptor tyrosine kinase pathways

SNT-2/FRS2β/FRS3 回避/接头蛋白对 EGF 受体酪氨酸激酶通路负调节的独特作用

• 发表时间: 2006
• 期刊: Oncogene 25
• 作者: Huang;L.;Watanabe;M.;Chikamori;M.;Kido;Y.;Yamamoto;T.;Shibuya;M.;Gotoh;N. and Tsuchida. N.
• 通讯作者: N. and Tsuchida. N.

Feedback inhibitors of epidermal growth factor receptor signaling pathways

表皮生长因子受体信号通路的反馈抑制剂

• 期刊: Int. J. Biocheuz. Cell Biol
• 作者: Gotoh;N.
• 通讯作者: N.

FRS2α^<2F/2F> mutant mice lack the carotid body and exhibit sympathetic ganglia and carotid sinus nerve abnormalities

FRS2α^<2F/2F>突变小鼠缺乏颈动脉体并表现出交感神经节和颈动脉窦神经异常

• 发表时间: 2008
• 期刊: Dev. Biol 314
• 作者: Kameda;Y.;Ito;M.;Nishimaki T. and Gotoh;N.
• 通讯作者: N.

Membrane-linked docking protein.

膜连接对接蛋白。

• 期刊: Encyclopedia of Cancer, 2nd Edition, Springer, Heidelberg, Germany, (掲載確定)
• 作者: Gotoh;N. and Tsuchida;N.
• 通讯作者: N.