Functional analysis of the adhesion GPCR class in Drosophila

粘附- gpcr （agpcr）具有高度模块化的蓝图，可以通过七螺旋跨膜单元（7TM）实现典型的g蛋白和β -阻滞蛋白信号传导，以及由大细胞外结构域介导的粘附和靶标识别。与其他GPCR家族不同，agpcr主要与邻近细胞或细胞外基质呈现的不溶性配体结合。配体性质和明显的受体几何形状可能反映了agpcr感知机械线索的能力，这在GPCR领域是一种不寻常的感觉模式。几项研究已经证明了agpcr在机械生物学现象中的功能，然而这些受体如何运作的几个主要机制方面，它们在响应机械刺激时触发的信号级联反应，以及这些信号如何被实施到细胞程序中以调节其生理学尚不清楚。此外，最近关于亲Latrophilin/dCirl的研究表明，ecd的尺寸塑造了其机械感受谱，而对亲Latrophilin/dCirl mRNA的选择性剪接产生的受体同种异构体在ecd大小上差异很大。本项目利用果蝇作为体内试管，研究天然发生的dcirl受体同种异构体的生物学相关性，特别关注其机械传感和信号传导能力。我们还将探索agpcr采用替代信号通路来塑造细胞行为的可能性。该项目的第二部分重点关注两个新发现的未被发现的agpcr （cg11318和CG15556）的功能表征。最后，我们将探讨它们是否在体内的机械生物学环境中起作用，如果是的话，如何整合这些输入来修改表达组织的生物学。

Adhesion-GPCRs (aGPCRs) possess a highly modular blueprint thatenables canonical G-protein and beta-arrestin signaling through aheptahelical transmembrane unit (7TM) as well as adhesion andtarget recognition mediated by large extracellular domains. In contrastto other GPCR families, aGPCRs engage primarily with insolubleligands presented by adjacent cells or the extracellular matrix. Theligand nature and the conspicuous receptor geometry may reflect thecapacity of aGPCRs to sense mechanical cues, an unusual sensorymodality within the GPCR realm. Several studies have demonstratedaGPCR function in mechanobiological phenomena, however severalprincipal mechanistic aspects of how these receptors operate, whichsignaling cascades they trigger in response to mechanical stimulationand finally how these signals are implemented into the cellularprogram to modulate its physiology are unknown. Furthermore, recentwork on Latrophilin/dCirl indicates that the dimension of the ECDshapes its mechanoceptive profile and that alternative splicing ofLatrophilin/dCirl mRNA yields receptor isoforms that vary greatly inECD size. This project utilizes Drosophila as an in vivo test tube toinvestigate the biological relevance of natively occuring dCIRLreceptor isoforms with a particular focus on their mechanosensingand signaling capabilities. We will also explore the possibility thataGPCRs employ alternative signaling routes to shape cellularbehavior. The second part of this project focuses on the functionalcharacterization of two newly identified, unsought aGPCRs (CG11318and CG15556). Finally, we will explore if they operate inmechanobiological contexts in vivo and if so how these inputs areintegrated to modify the biology of the expressing tissues.