SECRETS

The precise localization of receptors opposite neurotransmitter release sites is key to synaptic function. Extracellular scaffolding proteins are specialized proteins from the extracellular matrix that play a central role in positioning postsynaptic receptors, along with adhesion molecules and intracellular scaffolding proteins. The secretion of extracellular scaffolding proteins at synapses is thus essential to ensure neurotransmission, yet their trafficking and secretory pathways remain mostly uncharacterized. I propose to focus on two extracellular scaffolding proteins that are required for the localization of acetylcholine and GABA receptors at C. elegans neuromuscular junctions: the ADAMTS-like Punctin/MADD-4 and the ortholog of collagens XV/XVIII, CLE-1. My aim is to characterize the secretory routes of these two extracellular scaffolding proteins and investigate their dynamics by following 3 primary objectives. First, I will identify the molecular components involved at various stages of their trafficking and secretory pathways, using a combination of candidate-based and unbiased approaches. The factors identified will then be characterized, in particular to determine at which step the secretion pathway is altered in their absence. Second, I will visualize their transport along axons using in vivo imaging techniques and determine the identity of the vesicle transporting these proteins. Third, I will assess their turnover at synapses by measuring their rates of diffusion, neosynthesis and degradation. This project will provide fundamental insights into secretory pathways of extracellular scaffolding proteins, with broader implications for understanding synaptic function and its disruption in diseases such as synaptopathies.