PROJECT SUMMARY/ABSTRACT
Neurological and neurodegenerative disorders characterized by imbalances in synaptic transmission are often
linked to oxidative damage. Modification of synaptic signaling in the face of damage is critical for nervous
system function. Inter-tissue signaling is key to stress-induced synaptic modulation, but is not fully understood.
My long-term goal is to determine the molecular mechanisms controlling synaptic transmission in the presence
and absence of oxidative stress. G protein-coupled receptors (GPCRs) are regulators of synaptic transmission
and multi-tissue stress responses, yet the details of relevant GPCR pathways are largely unknown. Recent
work from my lab and others identified roles for the conserved GPCR FSHR-1 in regulating neuromuscular
signaling and oxidative stress responses. FSHR-1 is the sole C. elegans homolog of a family of mammalian
glycopeptide (GP) hormone receptors that control gonad development and function; Fshr deficiency is linked to
depression and brain oxidative stress in mice. In C. elegans, intestinal FSHR-1 promotes organism survival
during infection and oxidative stress; neuronal FSHR-1 can cell non-autonomously regulate intestinal oxidative
stress responses. My lab found that fshr-1 null animals have neuromuscular defects exacerbated by oxidative
stress, but where and how FSHR-1 regulates synaptic signaling under normal or stress conditions and the
mechanisms by which FSHR-1 is activated are unknown. The objective of this proposal is to determine how
FSHR-1 controls signaling at the C. elegans neuromuscular junction (NMJ) via activities in multiple cell types in
the presence and absence of oxidative stress. My preliminary data indicate FSHR-1 can act in neurons and the
intestine to promote muscle excitation. Our data further indicate this effect may be due to FSHR-1’s ability to
act cell non-autonomously to promote cholinergic synaptic vesicle release from motor neurons and suggest a
candidate GP ligand and downstream signaling pathways FSHR-1 may use exert to its effects at the NMJ. My
central hypothesis is that FSHR-1 acts in a subset of non-NMJ cells downstream of the -GP FLR-2 and/or
other peptide ligands to activate pathways involving GS and/or the lipid kinase SPHK-1 to indirectly promote
acetylcholine release and muscle excitation. Aim 1 will use genome editing, fluorescence localization and
calcium imaging, cell-specific protein degradation, and behavior to determine neuronal and non-neuronal sites
of FSHR-1 action in controlling NMJ function in normal and oxidative stress conditions. Aim 2 will use genetics,
imaging, and behavior to determine if downstream FSHR-1 effectors in other contexts mediate FSHR-1’s
effects on NMJ activity. Aim 3 will use complementary genetic epistasis and biochemical approaches to identify
FSHR-1 ligands relevant for its NMJ effects. This research is innovative in its use of a whole animal model to
explore inter-tissue signaling by a conserved GPCR regulating synaptic transmission in diverse conditions. It is
significant in defining novel roles for FSHR-1, which controls diverse processes across phylogeny, and may lay
groundwork for new therapies for synaptic dysfunction and oxidative stress, hallmarks of aging and disease.
