Fig 8. Hypothesized mechanism for FSHR-1 cross-tissue regulation of neuromuscular function.

Our data support a model in which FSHR-1 acts in distal tissues, including the intestine, and possibly glia or head neurons, to promote neurotransmitter release from cholinergic body wall motor neurons leading to body wall muscle excitation. This cell non-autonomous regulation of neuromuscular function likely requires secretion of currently unknown molecules from the intestine or other distal tissues in response to FSHR-1 activation that, in turn, act on unknown receptors on the cholinergic motor neurons to promote synaptic vesicle release through effects on UNC-10/RIM. Results of our epistasis experiments further suggest that FSHR-1 is activated by the glycoprotein ligands, GPLA-1/GPA2 and GPLB-1/GPB5. Known effectors of FSHR-1 in other contexts, GSA-1, ACY-1, and SPHK-1, act downstream of FSHR-1 in the intestine during neuromuscular junction regulation; however, further studies will be required to determine whether these molecules also act in motor neurons themselves or other distal tissues following FSHR-1 activation. Created in BioRender. BioRender.com/u21o416.