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

对接蛋白FRS2α是成纤维细胞生长因子（FGF）信号传导的主要介质。然而，FRS2α在体内的生理作用尚不清楚。我们发现frs2 α-缺失小鼠胚胎存在前后轴（a -p）形成缺陷，发育迟缓，导致E8.0致胚胎死亡。我们证明FRS2α对于维持自我更新的滋养细胞干细胞（TS）细胞在胚胎外外胚层（ExE）中响应FGF4是必不可少的，而胚胎外胚层（ExE）产生胎盘组织。通过分析嵌合胚胎。我们发现FRS2α也在原肠胚形成过程中通过原始条纹的细胞运动中发挥作用。此外，实验表明，Bmp4在TS细胞中的表达受MAP激酶依赖性FGF4刺激的控制。此外，在frs2 α-缺失的胚胎中，ExE中Bmp4的表达和外胚层中Smadl/5的激活均降低。这些实验强调了FRS2α的关键作用。在胚胎发育过程中介导了更多的过程，并揭示了FGF和Bmp4信号通路在胚胎早期发生中的潜在新联系。晶状体和视网膜的早期发育依赖于胚胎表面外胚层和视神经泡神经上皮之间的相互诱导作用。FGF信号传导参与了这种信号交换。我们通过分析FRS2α的Grb2结合位点（FRS2α ^<4F>）或Shp2结合位点（FRS2α ^<2F>）携带点突变的小鼠的表型，探索FRS2α下游信号通路在眼睛发育中的作用。FRS2α^<4F/4F>小鼠早期眼发育正常，而FRS2α^< 2F/2F>胚胎均出现眼发育缺陷，出现无眼或小眼。与FRS2α在FGF信号传导中的关键作用一致，FRS2α ^<2F/2F>胚胎中活化的ERK水平显著低于野生型胚胎。此外，晶状体诱导分子标记Pax6和Six3在Frs2α^<2F/2F>推定晶状体外胚层的表达降低。同样，ChxlO和Bmp4的表达；FRS2α^<2F/2F>小鼠视泡中视网膜前体增殖和晶状体发育所需的基因也分别减少。这些实验表明FRS2α中的特定酪氨酸残基在眼睛发育中发挥重要作用，并提示FGFR-FRS2α-Shp2-MAPK信号通路位于诱导晶状体和视网膜的关键基因产物的上游。少

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