Feeding state (fed vs starved) and food availability can dramatically alter an animals chemosensory response to chemicals in its environment. Dynamic changes in the expression levels of chemoreceptor genes is observed in fish, insects and nematodes, and may be a general mechanism underlying the long-term changes in chemosensory behaviors observed in starved animals. Our previous work found that the expression of a candidate chemoreceptor, srh-234, in the ADL sensory neuron type is modulated by starvation. We showed that sensory- and circuit-mediated regulation of srh-234 is dependent on cell-autonomous pathways acting in ADL, such as KIN-29, DAF-2, OCR-2 and calcium signaling, circuit inputs from RMG interneurons mediated by NPR-1 signaling, and neuronal outputs of ADL. To further investigate how starvation modulates chemoreceptor gene levels, we dissected the cis-regulatory sequences driving srh-234 expression. We found that a putative MEF-2 binding site sequence is required for starvation-induced downregulation of srh-234 expression, while a E-box sequence motif in close proximity of the MEF-2 site is required to promote srh-234 expression in ADL. In mammals, the MEF2 transcription factor is known to interact with basic helix-loop-helix transcription (bHLHs) factors at E-box sites to regulate gene expression. We therefore performed a systematic analysis of bHLH factors, and identified HLH-2, HLH-3, MXL-3 and HLH-30 as potential regulators of srh-234 expression. Mutations in either hlh-2, hlh-3 or mxl-3 reduce srh-234 expression in fed conditions, while hlh-30 suppresses the starvation-induced downregulation of srh-234, which is dependent on DAF-2 signaling acting in ADL. Since MXL-30/HLH-30 are known to play antagonistic roles in the intestine to modify autophagy in response to starvation, we explored their site of action in regulating srh-234. We found that MXL-3 acts in intestinal tissues to regulate srh-234 in ADL neurons. These results suggest that during starvation transcriptional changes in the intestine mediated by MXL-3/HLH-30 are communicated probably via insulin signals to ADL neurons to regulate srh-234 expression. Thus, our results provide a brain-gut interaction for modulating chemoreceptor gene expression as a function of feeding state.
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