Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans

Longjun Pu, Jing Wang, Qiongxuan Lu, Lars Nilsson, Alison Philbrook, Anjali Pandey, Lina Zhao, Robin van Schendel, Alan Koh, Tanara V. Peres, Weheliye H. Hashi, Si Lhyam Myint, Chloe Williams, Jonathan D. Gilthorpe, Sun Nyunt Wai, Andre Brown, Marcel Tijsterman, Piali Sengupta, Johan Henriksson () and Changchun Chen ()
Additional contact information
Longjun Pu: Umeå University
Jing Wang: Umeå University
Qiongxuan Lu: Umeå University
Lars Nilsson: Umeå University
Alison Philbrook: Brandeis University
Anjali Pandey: Brandeis University
Lina Zhao: Umeå University
Robin van Schendel: Leiden University Medical Center
Alan Koh: MRC Laboratory of Medical Sciences
Tanara V. Peres: MRC Laboratory of Medical Sciences
Weheliye H. Hashi: MRC Laboratory of Medical Sciences
Si Lhyam Myint: Umeå University
Chloe Williams: Umeå University
Jonathan D. Gilthorpe: Umeå University
Sun Nyunt Wai: Umeå University
Andre Brown: MRC Laboratory of Medical Sciences
Marcel Tijsterman: Leiden University Medical Center
Piali Sengupta: Brandeis University
Johan Henriksson: Umeå University
Changchun Chen: Umeå University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C. elegans. These two mutant libraries enable effective deorphanization of chemoreceptors, and characterization of receptors for neuropeptides in various cellular processes. Mutating a set of closely related GPCRs in a single strain permits the assignment of functions to GPCRs with functional redundancy. Our analyses identify a neuropeptide that interacts with three receptors in hypoxia-evoked locomotory responses, unveil a collection of regulators in pathogen-induced immune responses, and define receptors for the volatile food-related odorants. These results establish our GPCR and neuropeptide mutant libraries as valuable resources for the C. elegans community to expedite studies of GPCR signaling in multiple contexts.

Date: 2023
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DOI: 10.1038/s41467-023-44177-z

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