The Role of Fgf Signaling in Vertebrate Development

Fgf 信号传导在脊椎动物发育中的作用

• 批准号: 8348982
• 负责人: MARK B LEWANDOSKI
• 金额: $ 40.3万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8348982
• 关键词: 3' Untranslated Regions; Alleles; Behavior; Biological; Biology; Blood Vessels; Cell Death; Cell Differentiation process; Cell Maintenance; Cells; Complex; Dermis; Development; Disease; Embryo; Embryonic Development; Endothelial Cells; Evolution; Family; Fibroblast Growth Factor; Gene Expression; Genes; Genetic; Goals; Growth Factor Gene; Hindlimb; Human; Knock-in Mouse; Knowledge; Ligands; Limb Development; Malignant Neoplasms; Malignant neoplasm of prostate; Mesoderm; Modeling; Molecular; Mus; Muscle; Pathway interactions; Play; Positioning Attribute; Process; Publications; Publishing; Reporter; Role; Signal Transduction; Somites; Staging; Stem cells; Testicular Neoplasms; Tissues; Undifferentiated; WNT Signaling Pathway; Work; allantois; cancer therapy; external genitalia; genetic analysis; human DICER1 protein; insight; interest; malignant breast neoplasm; migration; mutant; myogenesis; premature; somitogenesis; tool; tumorigenesis; vasculogenesis; vertebra body

The long term goal of this project is to understand how a the important family of signaling ligands, called Fibroblast Growth Factors (FGFs), control a wide spectrum of cell biological behaviors such as proliferation, cell death, migration, stem cell maintenance and gene expression. In particular we use complex mouse genetics to understand the role of FGF signaling in mesodermal lineages with a special emphasis on extension of the body axis and formation of somites (segmented mesodermal segments that are the building blocks of vertebrate muscle, dermis and vertebral bodies). Our work has made clear that genetic redundancy is an important aspect of this biology; therefore all work in this project emerges from an effort to comprehensively characterize the genetic redundancy of FGF signaling in the mesodermal lineage. Such work is relevant to many cases of cancer where more than one FGF gene may be damaged. To achieve this, we needed to generate and characterized important Cre mouse lines, which are tools that allow the control of gene expression in the early embryo. These include TCre (expressed in the early emerging nascent mesoderm), TCre-Ert2 (activatable in emerging nascent mesoderm at all embryonic stages) and Tbx4-Cre (expressed in a posterior mesodermal domain that includes the allantois, hindlimb, and external genitalia(Dev. Dyn., 2011 in press,). TCre in particular has had a major impact on the field, being essential in about 20 publications, with three published this year(Dev. Biol., 2011 349:395, Dev. Biol., 2011 351:254, (PNAS, 2011 108:4018) and two publications in press. In FY 2011, as part of our general interest in early development, in collaborative studies we have helped to define the role of Pitx2 in extraocular myogenesis (Dev. Biol., 2011 349:395) and Dicer in somitogenesis (Dev. Biol., 2011 351:254). In FY 2011 we also published a major finding that defined which FGF ligands control the differentiation of cells that will form somites (PNAS, 2011 108:4018). In 2005 we had published the surprising insight that Fgf8 not required for this process, although a body of high profile work had placed it in a central position in current models. We showed that Fgf8, together with Fgf4, are required for essential aspects of somitogenesis: expression of oscillating gene domains, WNT pathway genes and markers of undifferentiated presomitic mesoderm. Importantly, we demonstrated the premature differentiation of the entire presomitic mesoderm. By examining similar mutants in which we genetically restored WNT signaling, we demonstrated that FGF signaling operates independently of WNT signaling in this process. This functional redundancy that we uncovered has implications for cancer as both FGFs have been found to be aberrantly active in testicular tumors. Furthermore this redundancy has implications for evolution as the same FGFs play compensatory roles in limb development. In FY2011, in a collaborative study, we also published (Dev Dyn, in press) the extensive characterization of a mouse line previously generated, but incompletely described, that carries an allele of Tbx4 in which Cre had been knocked in into the genes 3 untranslated region. Most notably, we determined that, despite the requirement for Tbx4 in allantoic vasculogenesis, the presumptive endothelial cells of the allantois do not express Tbx4 and Tbx4-Cre tracing, via activation of Cre reporters, revealed that the umbilical vasculature lineage never expressed Tbx4. These results imply that endothelial lineages are segregated prior to the onset of vasculogenesis, and demonstrate a role for the peri-vascular tissue in vasculogenesis.

该项目的长期目标是了解一个重要的信号配体系列（称为成纤维细胞生长因子（FGF））如何控制各种细胞生物学行为，例如增殖，细胞死亡，迁移，干细胞维持和基因表达。特别是我们使用复杂的小鼠遗传学来了解FGF信号在中胚层谱系中的作用，特别强调了身体轴的扩展和体子的形成（分段的中胚层段，这是椎骨肌肉，真皮和椎体的构造块）。我们的工作清楚地表明，遗传冗余是该生物学的重要方面。因此，该项目中的所有工作都从全面表征中胚层谱系中FGF信号的遗传冗余的努力中出现。这种工作与许多癌症病例有关，其中一个以上的FGF基因可能损坏。为了实现这一目标，我们需要生成和表征重要的CRE小鼠系，这是允许在早期胚胎中控制基因表达的工具。其中包括TCRE（在早期新兴的中胚层中表达），TCRE-ERT2（在所有胚胎阶段都可以在新兴的新生中胚层中激活）和TBX4-CRE（在包括allantois，Hindimb和Hindlimb和Hindimb，Hindimb和Hindlimb，Hindlimb和dep dev的后胚层中表达） 。 2011：351：254，（PNAS，2011年108：4018）和2011财年的两份出版物，作为我们对早期发展的一般兴趣的一部分，我们帮助定义了Pitx2在外部肌发生中的作用。 ，2011年108：4018）。我们表明，FGF8与FGF4一起是体质发生的基本方面所必需的：振荡基因结构域的表达，Wnt途径基因和未分化的前胚层中胚层的标志物。重要的是，我们证明了整个前中胚层的过早差异。通过检查我们从基因恢复Wnt信号传导的类似突变体，我们证明了FGF信号在此过程中独立于Wnt信号传导。我们发现的这种功能冗余对癌症具有影响，因为两种FGF在睾丸肿瘤中都异常活跃。此外，这种冗余对进化具有影响，因为同一FGF在肢体发育中起着补偿性作用。在2011财年，在一项合作研究中，我们还发表了（开发dyn，印刷中）先前生成但未完全描述的小鼠线的广泛表征，该线载有TBX4等位基因，该等位基因将CRE撞入基因3未经翻译的基因中。地区。最值得注意的是，我们确定，尽管在藻类血管发生中需要进行TBX4，但Allantois的假定内皮细胞并未表达TBX4和TBX4-CRE跟踪，通过激活CRE报道器，表明Umbilical Vasculical Vasculical血管谱系从未表达过TBX4。这些结果表明，在血管生成开始之前，内皮谱系被隔离，并证明了血管周围组织在血管生成中的作用。