OGT-1 Collaborates with Insulin Signaling Pathway to Regulate Synaptic Assembly

Synaptic formation and maintenance are precisely regulated, and their defects often lead to neurodevelopmental or neurodegenerative disorders. In addition to intrinsic molecular pathways, synaptic structure and function are also regulated by nutrient-related signals. O-GlcNAc transferase (OGT), a nutrient sensor that catalyzes O-GlcNAcylation, is highly abundant in the nervous system and required for synaptic plasticity, learning and memory. However, if and how OGT is involved in presynaptic assembly are largely unknown. In this study, we found that OGT-1 is required for presynaptic assembly specifically in a subset of neurons in the nematode C. elegans. Mechanistically, depending on its glycosyltransferase activity, OGT-1 acts downstream of the insulin receptor DAF-2 and upstream of the FOXO transcription factor DAF-16. Additionally, we also found that OGT-1 is required for associative learning. Our findings indicate that O-GlcNAc signaling collaborates with insulin signaling pathway to regulate presynaptic assembly, providing a potential molecular mechanism underlying the metabolic-related neurological disorders.