Transcriptional regulation of neuropeptide receptors underlies context-dependent adaptation in Drosophila melanogaster.

Neuropeptides (NPs) and their receptors (NPRs) play critical roles in modulating physiological processes and behaviors across species. While the transcriptional regulation of NP genes has been extensively studied, how NPRs contribute to context-dependent behavioral plasticity remains poorly understood. Here, we investigate the genomic features and expression patterns of NPRs in Drosophila melanogaster, leveraging comparative genomics, single-cell RNA sequencing (scRNA-seq), transcription factor (TF) network analysis, and empirical validation to uncover the regulatory mechanisms that involve NPRs and play roles in context-dependent adaptation. We demonstrate that NPR genes exhibit more complex cis-regulatory landscapes, with greater numbers of enhancers compared to NP genes. Also, NPRs are regulated via a broader network of TFs, particularly in response to environmental and physiological cues such as temperature shifts. Through analysis of scRNA-seq data and qRT-PCR, we show that the expression level of NPRs is dynamically modulated in a context-dependent manner, while NP levels remain relatively stable. This "NPR-biased" gene regulation is evident across diverse combinations of NP-NPR pairs, with a distinct pattern of TF control in the head and body of D. melanogaster. Furthermore, the expression level of NPR genes increases during aging of the fly, suggesting a key role in aging and developmental processes. Our findings highlight the importance of NPR transcriptional control in shaping neuropeptidergic signaling and adaptive behaviors.