Role of FGF Signaling in Controlling Cell Movements During Drosophila Development

描述(申请人提供)：成纤维细胞生长因子(成纤维细胞生长因子)信号影响许多不同的细胞功能，对支持胚胎发育很重要。成纤维细胞生长因子配体是一种多肽生长因子，能激活与其受体的胞内区相关的酪氨酸激酶活性，从而在细胞内引发信号反应。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；而另一种机制是，只有所有可能的配体-受体相互作用的子集是起作用的。我们已经发现，在果蝇体内，六种可能的FGFR-FGFR相互作用中只有三种：Pyramus和Thisbe FGFR配体分别支持无情的FGFR激活，而只有FGFR配体无分支支持激活呼吸的FGFR。在脊椎动物中，配体-受体蛋白相互作用的特殊性当然也限制了功能性的FGF-FGFR组合，然而，脊椎动物系统仍然相当复杂，可能有120多种组合。我们认为，更简单的果蝇模型系统特别适合于促进对成纤维细胞生长因子信号在发育过程中作用的分子机制的理解，特别是在集体细胞运动的协调方面。在果蝇胚胎中，通过无情的FGFR的信号对于控制原肠发育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是重要的；这些重要的中胚层细胞运动是支持心脏和内脏中胚层发育所必需的，在没有成纤维细胞生长因子信号的情况下，这些重要的中胚层细胞运动是混乱的。此外，我们还利用果蝇系统获得了证据，表明成纤维细胞生长因子配体的选择、水平和切割状态都可以影响FGFR依赖的输出。总而言之，我们的结果支持这样的观点，即与脊椎动物领域普遍接受的信念相反，同时作用于激活同一受体的成纤维细胞生长因子配体并不是多余的，相反，它表明成纤维细胞生长因子配体在果蝇胚胎中发挥着不同的作用。我们计划利用更简单的果蝇模型系统来发现更多关于这一重要信号通路是如何调控的新见解，特别是探索成纤维细胞生长因子信号和细胞黏附调节之间以前被低估的联系。这项研究有三个目的：(1)通过调节细胞的粘附性来测试成纤维细胞生长因子信号支持细胞运动的观点；(2)通过活体成像研究了解成纤维细胞生长因子信号在支持细胞运动中的作用；(3)研究成纤维细胞生长因子活性是如何受蛋白质分解和/或配体扩散范围的差异调节的。这项在果蝇中的研究将为调节成纤维细胞生长因子信号提供新的见解，这一点很重要，因为人类的许多疾病和发育不良都与通过这一途径的异常信号有关。在人类中，不受控制的细胞迁移可能会对心脏和血管发育造成有害影响，也会导致转移。由于所有这些原因，了解成纤维细胞生长因子信号如何控制协调细胞迁移具有潜在的深远影响。

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.