Functional analysis of the adhesion GPCR class in Drosophila
Adhesion-GPCRs (aGPCRs) possess a highly modular blueprint that enables canonical G-protein and beta-arrestin signaling through a heptahelical transmembrane unit (7TM) as well as adhesion and target recognition mediated by large extracellular domains. In contrast to other GPCR families, aGPCRs engage primarily with insoluble ligands presented by adjacent cells or the extracellular matrix. The ligand nature and the conspicuous receptor geometry may reflect the capacity of aGPCRs to sense mechanical cues, an unusual sensory modality within the GPCR realm. Several studies have demonstrated aGPCR function in mechanobiological phenomena, however several principal mechanistic aspects of how these receptors operate, which signaling cascades they trigger in response to mechanical stimulation and finally how these signals are implemented into the cellular program to modulate its physiology are unknown. Furthermore, recent work on Latrophilin/dCirl indicates that the dimension of the ECD shapes its mechanoceptive profile and that alternative splicing of Latrophilin/dCirl mRNA yields receptor isoforms that vary greatly in ECD size. This project utilizes Drosophila as an in vivo test tube to investigate the biological relevance of natively occuring dCIRL receptor isoforms with a particular focus on their mechanosensing and signaling capabilities. We will also explore the possibility that aGPCRs employ alternative signaling routes to shape cellular behavior. The second part of this project focuses on the functional characterization of two newly identified, unsought aGPCRs (CG11318 and CG15556). Finally, we will explore if they operate in mechanobiological contexts in vivo and if so how these inputs are integrated to modify the biology of the expressing tissues.