The Conserved C. elegans Glycopeptide Hormone Receptor FSHR-1 Regulates Cholinergic Neurotransmission through Cell Non-Autonomous Signaling

Core Concepts

The glycopeptide hormone receptor FSHR-1 in C. elegans acts in a cell non-autonomous manner, primarily through the intestine, to modulate cholinergic neurotransmission and neuromuscular function.

Abstract

The study investigates the mechanisms by which the conserved C. elegans glycopeptide hormone receptor FSHR-1 regulates neuromuscular signaling. Key findings:

Loss of fshr-1 leads to defects in neuromuscular behaviors, including resistance to the acetylcholinesterase inhibitor aldicarb and reduced swimming and crawling.

The neuromuscular defects in fshr-1 mutants are accompanied by an accumulation of synaptic vesicles in cholinergic motor neurons, suggesting decreased synaptic vesicle release. This is confirmed by reduced fluorescence recovery after photobleaching of the synaptic vesicle marker SNB-1::Superecliptic pHluorin.

The localization of the active zone protein UNC-10/RIM is altered in cholinergic synapses of fshr-1 mutants, providing a potential mechanism for the synaptic vesicle release defects.

Re-expression of fshr-1 in the intestine, as well as in glial cells and neurons, can restore neuromuscular function in fshr-1 mutants. Intestinal expression is both necessary and sufficient for the regulation of cholinergic synaptic vesicle localization.

Genetic interaction studies suggest that the FSHR-1 signaling pathway, including the Gα, adenylyl cyclase, and sphingosine kinase effectors, as well as the glycoprotein hormone subunit orthologs GPLA-1/GPA2 and GPLB-1/GPB5, are important for FSHR-1 modulation of neuromuscular function.

Overall, the results demonstrate that the conserved glycopeptide hormone receptor FSHR-1 acts in a cell non-autonomous manner, primarily through the intestine, to regulate cholinergic neurotransmission and neuromuscular function in C. elegans.

Stats

"Approximately 20% of fshr-1 mutant worms were paralyzed after 100 minutes on aldicarb, compared with approximately 65% of wild type worms."
"fshr-1 mutant animals have reduced body bends per minute (∼165) compared to wild type (∼195) in swimming assays."
"GFP::SNB-1 puncta intensity at cholinergic presynaptic terminals of fshr-1 mutants is increased by approximately 40% compared to controls."
"Synaptic vesicle fluorescence recovery after photobleaching is reduced by ∼35% in fshr-1 mutants compared to wild type."
"GFP::UNC-10 fluorescence intensity at cholinergic synapses is increased by ∼55% in fshr-1 mutants."

Quotes

"Restoration of FSHR-1 to the intestine is sufficient to restore neuromuscular activity and synaptic vesicle localization to fshr-1-deficient animals."
"Intestine-specific knockdown of FSHR-1 reduces neuromuscular function, indicating FSHR-1 is both necessary and sufficient in the intestine for its neuromuscular effects."
"Genetic interaction studies provide evidence that downstream effectors gsa-1/GαS, acy-1/adenylyl cyclase and sphk-1/sphingosine kinase and glycoprotein hormone subunit orthologs, GPLA-1/GPA2 and GPLB-1/GPB5, are important for FSHR-1 modulation of the NMJ."

Key Insights Distilled From

Cell non-autonomous signaling through the conserved C. elegans glycopeptide hormone receptor FSHR-1 regulates cholinergic neurotransmission

by Buckley,M., ... at www.biorxiv.org 02-12-2024

https://www.biorxiv.org/content/10.1101/2024.02.10.578699v1

Deeper Inquiries

How might the cell non-autonomous signaling mechanisms involving FSHR-1 in the intestine be integrated with other known pathways that regulate neuromuscular function, such as those involving neuropeptides or gliotransmitters?

The cell non-autonomous signaling mechanisms involving FSHR-1 in the intestine can be integrated with other pathways that regulate neuromuscular function through complex crosstalk between different tissues and signaling molecules. In the context of neuromuscular function, the intestine acts as an endocrine regulator, releasing signaling molecules that can influence synaptic transmission at the neuromuscular junction (NMJ). FSHR-1 in the intestine may modulate the release of neuropeptides or gliotransmitters that can impact cholinergic neurotransmission at the NMJ. Neuropeptides released from neurons or other tissues can act as neuromodulators, influencing synaptic activity and neurotransmitter release. By regulating the release of neuropeptides, FSHR-1 in the intestine may indirectly affect cholinergic neurotransmission at the NMJ. Similarly, gliotransmitters released from glial cells can also modulate synaptic transmission and neuronal activity. FSHR-1 signaling in the intestine may influence the release of gliotransmitters, thereby affecting neuromuscular function through glia-neuron communication. Overall, the integration of FSHR-1 signaling in the intestine with pathways involving neuropeptides and gliotransmitters provides a mechanism for coordinated regulation of neuromuscular function across different tissues.

How might the cell non-autonomous signaling mechanisms involving FSHR-1 in the intestine be integrated with other known pathways that regulate neuromuscular function, such as those involving neuropeptides or gliotransmitters?

The specific downstream signaling pathways and effectors through which FSHR-1 in the intestine modulates cholinergic neurotransmission at the neuromuscular junction involve a cascade of molecular events that regulate synaptic vesicle release and neurotransmitter activity. Upon activation of FSHR-1 in the intestine, signaling pathways are initiated that lead to the modulation of cholinergic neurotransmission at the NMJ. One potential downstream effector of FSHR-1 signaling is the activation of G protein-coupled receptors (GPCRs) that can trigger intracellular signaling cascades. These signaling cascades may involve the activation of second messengers such as cyclic adenosine monophosphate (cAMP), diacylglycerol (DAG), and Ca2+, which can regulate synaptic vesicle release and neurotransmitter activity. Additionally, FSHR-1 signaling may interact with other signaling pathways involved in neuromuscular function, such as those mediated by neuropeptides or gliotransmitters, to coordinate synaptic transmission at the NMJ. By influencing the localization and release of synaptic vesicles, FSHR-1 in the intestine plays a crucial role in modulating cholinergic neurotransmission and maintaining neuromuscular function.

Could the insights into FSHR-1 function in C. elegans provide clues about the potential roles of the conserved mammalian glycoprotein hormone receptors, such as FSHR, LHR, and TSHR, in regulating nervous system function and behavior?

The insights into FSHR-1 function in C. elegans could indeed provide valuable clues about the potential roles of conserved mammalian glycoprotein hormone receptors, including FSHR, LHR, and TSHR, in regulating nervous system function and behavior. The findings from studies on FSHR-1 in C. elegans suggest that glycoprotein hormone receptors, which are known to play key roles in reproductive and metabolic processes, may also have important functions in the nervous system. The involvement of FSHR-1 in modulating cholinergic neurotransmission and neuromuscular function highlights the potential neuroendocrine functions of glycoprotein hormone receptors in regulating synaptic activity and behavior. Given that mammalian glycoprotein hormone receptors are expressed in the nervous system and have been implicated in various neurological conditions, such as Alzheimer's disease and ADHD, the insights from C. elegans studies could shed light on the mechanisms by which these receptors influence nervous system function in mammals. Understanding the roles of glycoprotein hormone receptors in neuronal signaling and synaptic transmission may provide new avenues for investigating and potentially treating neurological disorders and cognitive impairments in humans.