Role of FGF Signaling in Controlling Cell Movements During Drosophila Development

FGF 信号在果蝇发育过程中控制细胞运动中的作用

基本信息

批准号：
8640199
负责人：
Angelike Stathopoulos
金额：
$ 32.47万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8640199
关键词：
Achondroplasia Adhesives Affect Behavior Belief Binding Biological Assay Biological Models Cell Adhesion Cell physiology Cell surface Cells Complex Craniosynostosis Development Diffusion Disease Dissection Drosophila genus Drosophila melanogaster Dysplasia Embryo Embryonic Development Epithelial Exhibits Fibroblast Growth Factor Fibroblast Growth Factor Receptors Gene Expression Genetic Techniques Goals Growth Factor Growth Factor Gene Heart Human Individual Lead Life Ligands Link Maintenance Malignant - descriptor Mesenchymal Mesoderm Mesoderm Cell Molecular Molecular Genetics Neoplasm Metastasis Neuronal Differentiation Organ Output Pathology Pathway interactions Pattern Process Protein Tyrosine Kinase Regulation Role Signal Pathway Signal Transduction Specificity Supporting Cell System Testing Tissue-Specific Gene Expression Vertebrates Visceral Wound Healing cell growth cell motility gastrulation in vivo imaging insight migration neuronal survival novel polypeptide public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): Fibroblast growth factor (FGF) signaling impacts a number of different cellular functions important for supporting embryonic development. FGF ligands are polypeptide growth factors that trigger tyrosine kinase activity associated with the intracellular domains of their receptors, and thereby elicit signaling responses within cells. Differential expression of genes encoding ligands and receptors is one mechanism by which signaling pathway activation is regulated; while another is that only a subset of all possible ligand-receptor interactions are functional. We have found that only three of six possible FGF-FGFR interactions are acting in Drosophila melanogaster: Pyramus and Thisbe FGF ligands each support activation of the FGFR Heartless, while only the FGF ligand Branchless supports activation of the Breathless FGFR. In vertebrates, specificity of ligand-receptor protein interactions also certainly limits functional FGF-FGFR combinations, nevertheless, the vertebrate system remains quite complex with over 120 combinations possible. We contend that the simpler Drosophila model system is particularly well-suited to advance understanding of the molecular mechanism by which FGF signaling acts during development and, in particular, in the coordination of collective cell movement. In Drosophila embryos, signaling through the Heartless FGFR is important for controlling mesoderm spreading during gastrulation and also, subsequently, for migration of caudal visceral mesoderm cells in the embryo; these important mesoderm cell movements, required to support cardial and visceral mesoderm development, are disorganized in the absence of FGF signaling. In addition, we have also acquired evidence using the Drosophila system that FGF ligand choice, levels, and cleavage-state can all affect FGFR-dependent outputs. Collectively, our results support the view that FGF ligands that act concurrently to activate the same receptor are not redundant, contrary to the generally accepted belief in the vertebrate field, and instead suggest that FGF ligands fulfill distinct roles in the Drosophila embryo. We plan to take advantage of the simpler Drosophila model system to uncover additional novel insights into how this important signaling pathway is regulated and, in particular, to explore a previously underappreciated link between FGF signaling and the regulation of cell adhesion. The study has three aims: (1) To test the idea that FGF signaling supports cell movement by regulating cells' adhesivity; (2) To obtain insight into the role of FGF signaling in supporting cell movement by conducting live in vivo imaging studies; (3) To investigate how FGF activity is regulated by proteolytic cleavage and/or differences in ligand diffusion range. This study in Drosophila will provide novel insight into regulation of FGF signaling, which is important as many diseases and dysplasias in humans relate to aberrant signaling through this pathway. Uncontrolled cell migration in humans can lead to detrimental effects on the heart and vasculature development as well as to metastasis. For all these reasons, understanding how coordinate cell migration is controlled by FGF signaling has the potential for far-reaching impact.

描述（由申请人提供）：成纤维细胞生长因子（FGF）信号传导影响许多对支持胚胎发育很重要的不同细胞功能。 FGF 配体是多肽生长因子，可触发与其受体的细胞内结构域相关的酪氨酸激酶活性，从而引发细胞内的信号传导反应。编码配体和受体的基因的差异表达是调节信号通路激活的一种机制。另一个是所有可能的配体-受体相互作用中只有一部分是有功能的。我们发现，六种可能的 FGF-FGFR 相互作用中只有三种在黑腹果蝇中起作用：Pyramus 和 Thisbe FGF 配体各自支持 FGFR Heartless 的激活，而只有 FGF 配体 Branchless 支持 Breathless FGFR 的激活。在脊椎动物中，配体-受体蛋白相互作用的特异性也肯定限制了功能性 FGF-FGFR 组合，尽管如此，脊椎动物系统仍然相当复杂，可能存在超过 120 种组合。我们认为，更简单的果蝇模型系统特别适合促进对 FGF 信号在发育过程中发挥作用的分子机制的理解，特别是在集体细胞运动的协调中。在果蝇胚胎中，通过 Heartless FGFR 发出的信号对于控制原肠胚形成过程中中胚层的扩散以及随后胚胎中尾部内脏中胚层细胞的迁移非常重要。这些支持心脏和内脏中胚层发育所需的重要中胚层细胞运动在缺乏 FGF 信号传导的情况下会被破坏。此外，我们还使用果蝇系统获得了证据，表明 FGF 配体的选择、水平和裂解状态都会影响 FGFR 依赖性输出。总的来说，我们的结果支持这样的观点，即同时激活相同受体的 FGF 配体并不是多余的，这与脊椎动物领域普遍接受的观点相反，而是表明 FGF 配体在果蝇胚胎中发挥不同的作用。我们计划利用更简单的果蝇模型系统来揭示关于如何调节这一重要信号通路的更多新见解，特别是探索以前未被充分认识的 FGF 信号传导与细胞粘附调节之间的联系。该研究有三个目的：（1）验证FGF信号通过调节细胞粘附性支持细胞运动的观点； (2) 通过进行活体成像研究，深入了解FGF信号在支持细胞运动中的作用； (3) 研究FGF活性如何通过蛋白水解裂解和/或配体扩散范围的差异来调节。这项在果蝇中的研究将为 FGF 信号传导的调节提供新的见解，这很重要，因为人类的许多疾病和发育不良都与通过该途径的异常信号传导有关。人类不受控制的细胞迁移会对心脏和脉管系统发育以及转移产生有害影响。出于所有这些原因，了解 FGF 信号传导如何控制协调细胞迁移可能会产生深远的影响。