Regulation of glutamate receptor trafficking by VER/VEGF receptors in the nervous system of C. elegans

点击翻译按钮获取中文摘要

This project studies how a molecule that was originally described as a blood vessel development growth factor also controls communication between nerve cells in the roundworm Caenorhabditis elegans. While all the molecular pathways studied here are present in vertebrate animals including humans, these experiments are conducted in roundworms because they have a compact and defined nervous system, are amenable to genetic manipulation and, in particular, do not have any blood vessels. This makes it possible to avoid confounding effects that changes in vascular development might indirectly have on neural development. Results from this project will advance scientific understanding of nerve cell signaling and plasticity; this research may also identify new genes and molecular pathways important for learning and memory. A complementary outreach plan will develop an instructional research module for use at local public high schools, and a full-semester neurobiology lab course for undergraduates where students have a real opportunity to generate new scientific knowledge that could develop into an independent research project. In the process of performing the proposed research aims, this project will also train graduate students and provide hands-on independent research opportunities for undergraduates, for educators, and for under-represented minorities in a dedicated summer program.The modulation of synaptic strength via activity-dependent changes in glutamate receptor (GluR) abundance at synapses is a major mechanism underlying learning and memory. While previous work has identified the molecular mechanisms that directly traffic GluRs to and from synapses, less is known about in-vivo secreted factors that act on these receptor trafficking pathways. Preliminary studies from the Principal Investigator’s laboratory have used an optogenetic glutamatergic behavior screen in C. elegans to identify the Vascular Endothelial Growth Factor Receptor (VEGFR) homologs ver-1 and ver-4, which are activated by the secreted VEGF homolog PVF-1. Data also suggest that VER-1 and VER-4, and the ligand PVF-1, regulate both cell surface levels of the GluR GLR-1 and glutamatergic behaviors in C. elegans. The goal of this proposal is to investigate whether regulated secretion of PVF-1/VEGF activates neuronal VER/VEGFR signaling to modulate GLR-1/GluR recycling to the cell surface, thereby impacting behavior. C. elegans is a particularly suitable organism for these studies because of their lack of vasculature, allowing these experiments on the neural effects of VEGFRs to be free of confounds from the vasculature. This work will elucidate the mechanisms by which VER signaling within neurons regulates GLR-1 trafficking, and how PVF-1 expression or secretion are regulated in vivo to modulate GLR-1 abundance and behavior. This study may reveal novel details about the fundamental and conserved mechanisms through which VEGFRs contribute to nervous system function.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.