Transmembrane channel-like proteins regulate crop size and contraction dynamics during Drosophila feeding

Feeding regulation in Drosophila involves complex interactions between mechanosensory and neuroendocrine pathways. Our study identified transmembrane channel-like (TMC) proteins as key regulators of crop size and contraction, functioning through distinct neuronal populations. They influence crop size via diuretic hormone, Dh44 -expressing neuroendocrine cells in the pars intercerebralis (PI) region and regulate crop contraction through the serotonin receptor 5-HT7. We found that TMC proteins are broadly expressed from the gut to the brain, reinforcing their role in the brain-gut axis. Mechanotransduction channels, including NompC, Piezo, and TMC, facilitate food ingestion, with TMC channels playing an additional role in food storage and transport. We noted the coexpression of piezo with Dh44 in only two neurons, indicating that at least two Dh44 cells are required for crop size regulation. Moreover, we identified Dh44R2 as the key receptor regulating crop size. Unlike DH44 and Piezo, TMC, 5-HT7, and TRPγ are essential for crop contraction, suggesting that these channels serve as therapeutic targets for regulating food intake. Our findings also support the involvement of a mechanosensory serotonergic pathway in regulating crop physiology, integrating sensory and neuroendocrine signals to control food storage and transport. These findings advance our understanding of the neuronal and molecular mechanisms underlying feeding behavior in Drosophila and provide a foundation for exploring conserved pathways that regulate food intake in other organisms, including mammals.