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Analysis of molecular mechanisms of development and physiological functions of mammals regulated by a docking protein

对接蛋白调控哺乳动物发育和生理功能的分子机制分析

基本信息

批准号：
14580691
负责人：
GOTOH Noriko
金额：
$ 2.3万
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：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580691/
关键词：
FRS2 docking protein FGF stem cells Bmp placenta knock out mice

项目摘要

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 … More 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

对接蛋白FRS 2 α是成纤维细胞生长因子（FGF）信号传导的主要介质。然而，FRS 2 α在体内的生理作用仍然未知。我们发现，Frs 2 α-null小鼠胚胎在前-后（A-P）轴形成方面存在缺陷，并且发育迟缓，导致E8.0的胚胎死亡。我们证明，FRS 2 α是维持自我更新的滋养层干细胞（TS）细胞响应FGF 4在胚外外胚层（ExE），产生胎盘组织的必要条件。通过分析嵌合体胚胎。我们发现FRS 2 α还在原肠胚形成期间通过原条的细胞运动中起作用。此外，实验表明TS细胞中的Bmp 4表达受MAP激酶依赖性FGF 4刺激的控制。此外，在FRS 2 α缺失的胚胎中，ExE中Bmp 4的表达和外胚层中Smadl/5的活化都降低。这些实验强调了FRS 2 α的关键作用。在介导 ...更多信息透镜和视网膜的早期发育依赖于胚胎表面外胚层和视泡神经上皮之间的相互诱导作用。FGF信号传导已经涉及这种信号交换。我们通过分析在FRS 2 α的Grb 2结合位点（Frs 2 α^）或Shp 2结合位点（Frs 2 α^）中携带点突变的小鼠的表型，探索FRS 2 α下游信号通路在眼睛发育中的作用<4F><2F>。虽然FRS 2 α^<4F/4F>小鼠表现出正常的早期眼发育，但所有Frs 2 α^<2F/2F>胚胎的眼发育都有缺陷，并表现出无眼或小眼。与FRS 2 α在FGF信号传导中的关键作用一致，FRS 2 α^<2F/2F>胚胎中活化的ERK水平显著低于野生型胚胎中观察到的水平。此外，在Frs 2 α^<2F/2F>假定的透镜外胚层中，透镜诱导的分子标记Pax 6和Six 3的表达降低。类似地，在FRS 2 α^<2F/2F>小鼠的视泡中，视网膜前体增殖和透镜发育所需的ChxlO和Bmp 4基因的表达也分别降低。这些实验证明FRS 2 α中的特定酪氨酸残基在眼发育中起重要作用，并表明FGFR-FRS 2 α-Shp 2-MAPK信号通路位于诱导透镜和视网膜的关键基因产物的上游。少