Heterotrimeric G proteins regulate planarian regeneration and behavior.

G protein-coupled receptors play broad roles in development and stem cell biology, but few roles for G protein-coupled receptor signaling in complex tissue regeneration have been uncovered. Planarian flatworms robustly regenerate all tissues and provide a model with which to explore potential functions for G protein-coupled receptor signaling in somatic regeneration and pluripotent stem cell biology. As a first step toward exploring G protein-coupled receptor function in planarians, we investigated downstream signal transducers that work with G protein-coupled receptors, called heterotrimeric G proteins. Here, we characterized the complete heterotrimeric G protein complement in Schmidtea mediterranea for the first time and found that seven heterotrimeric G protein subunits promote regeneration. We further characterized two subunits critical for regeneration, Gαq1 and Gβ1-4a, finding that they promote the late phase of anterior polarity re-establishment, likely through anterior pole-produced Follistatin. Incidentally, we also found that five G protein subunits modulate planarian behavior. We further identified a putative serotonin receptor, gcr052, that we propose works with Gαs2 and Gβx2 in planarian locomotion, demonstrating the utility of our strategy for identifying relevant G protein-coupled receptors. Our work provides foundational insight into roles of heterotrimeric G proteins in planarian biology and serves as a useful springboard towards broadening our understanding of G protein-coupled receptor signaling in adult tissue regeneration.