Role of FGF Signaling in Controlling Cell Movements During Drosophila Development

描述（由申请人提供）：成纤维细胞生长因子（FGF）信号传导影响许多不同的细胞功能，这些功能对支持胚胎发育很重要。FGF配体是多肽生长因子，其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应答。编码配体和受体的基因的差异表达是调节信号通路活化的一种机制;而另一种机制是所有可能的配体-受体相互作用中只有一部分是功能性的。我们已经发现，在果蝇中，六种可能的FGF-FGFR相互作用中只有三种起作用：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当然也限制了功能性FGF-FGFR组合，然而，脊椎动物系统仍然相当复杂，可能有超过120种组合。我们认为，更简单的果蝇模型系统特别适合于深入了解FGF信号在发育过程中作用的分子机制，特别是在集体细胞运动的协调中。在果蝇胚胎中，通过无情FGFR的信号传导对于控制原肠胚形成期间的中胚层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，需要支持胚胎和内脏中胚层发育，在没有FGF信号传导的情况下是无序的。此外，我们还获得了使用果蝇系统的证据，FGF配体的选择，水平和切割状态都可以影响FGF依赖的输出。总的来说，我们的研究结果支持这样的观点，即FGF配体，同时激活相同的受体是不是多余的，相反，在脊椎动物领域的普遍接受的信念，而是表明，FGF配体在果蝇胚胎中履行不同的角色。我们计划利用更简单的果蝇模型系统，以发现更多的新的见解，这一重要的信号通路是如何调节，特别是探索以前未被充分认识的FGF信号和细胞粘附调节之间的联系。这项研究有三个目标：（1）测试FGF信号传导通过调节细胞的粘附性来支持细胞运动的想法;（2）通过进行活体体内成像研究来深入了解FGF信号传导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切割和/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传导有关。人类不受控制的细胞迁移可导致对心脏和脉管系统发育的有害影响以及转移。由于所有这些原因，了解FGF信号传导如何控制协调细胞迁移具有深远影响的潜力。

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.