Elucidating the molecular mechanisms by which mammalian Latrophilin Adhesion GPCRs function in synapse formation in vivo

• Applicant: Daniel Matus
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505070089

There is a rising body of evidence that synaptic adhesion molecules play a crucial role in the generation, specification and maintenance of synapses, which in turn are fundamental for establishing the neuronal circuits and networks exerting the intricate functions of the mammalian brain. In this context, latrophilins stand out among other adhesion molecules since – as Adhesion G protein-coupled receptors (Adhesion GPCRs) – they combine the abilities of mediating transynaptic adhesion via their huge extracellular N termini and transducing signals across the plasma membrane by coupling to G proteins that activate intracellular signaling cascades. First insights into the structural features of latrophilins as well as synaptic interaction partners such as FLRTs and teneurins have emerged in recent years. However, data on the molecular requirements for the three mammalian latrophilin homologs to coordinately mediate synapse formation in vivo is still sparse. The goal of this project is therefore to deconstruct the molecular mechanisms by which latrophilins function in synapse formation in vivo.In particular, this study firstly aims to understand what molecular features define redundancy or complementarity of the three mammalian Latrophilin homologs. Thereby, each latrophilin homolog will be screened for roles in synapse formation to reveal a possible functional overlap and/or dissociation with other homologs. Subsequently, it will be analyzed whether subcellular restriction to specific dendritic domains or different binding affinities to ligands can cause differences in the functional spectrum of the three latorophilin homologs.Secondly, it is crucial to elucidate the architecture of the transsynaptic complexes that Latrophilins establish with other adhesion molecules. Since coincident binding of FLRTs and Teneurins to latrophilins has been shown to be essential for synapse formation in the hippocampus, this study will aim to discover whether the formation of such a transsynaptic complex is a common way of latrophilin function and can therefore be found in multiple different physiological contexts. Furthermore, it will be addressed whether one latrophilin molecule can simultaneously interact with both ligands or whether multiple receptors are needed to maintain the transsynaptic complex.Lastly, it is of interest, whether hallmark features of the Adhesion GPCR class such as receptor autoproteolysis within the extracellular N terminus and G protein-mediated signaling are relevant for latrophilin function in synaptogenesis in different physiological contexts. The latter is of special interest, since previous findings suggested latrophilin GPCR function activating cAMP-dependent intracellular signaling cascades to be essential in hippocampal synapse assembly.By addressing these goals, a comprehensive view of latrophilin function in synapse formation can be generated, which will further enhance our knowledge about how neuronal circuits develop in vivo.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Thomas Christian Südhof