Kernekoncepter
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.
Resumé
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.
Statistik
"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."
Citater
"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."