GABA-A signaling maintains melanocyte stem cell quiescence in larval zebrafish

Abstract

Adult stem cells (ASCs) contribute to long-term homeostasis and regeneration of many adult tissues. Some ASCs proliferate continuously, others remain quiescent awaiting activation. To identify pathways that regulate ASC quiescence and tissue homeostasis, we study melanocyte stem cells (MSCs) that drive vertebrate pigmentation. In larval zebrafish, MSCs are quiescent, but can be recruited to regenerate the larval pigment pattern following melanocyte ablation. Through pharmacological experiments, we found that inhibition of GABA-A receptor function, specifically the GABA-A rho subtype, induces excessive melanocyte production in larval zebrafish. Conversely, pharmacological activation of GABA-A inhibited melanocyte regeneration. We used CRISPR to generate two mutant alleles of gabrr1, a subtype of GABA-A. Both alleles exhibited robust melanocyte overproduction, while conditional overexpression of gabrr1 inhibited larval melanocyte regeneration. Our data suggest that gabrr1 signaling is necessary and sufficient to maintain MSC quiescence and prevent excessive pigmentation of the larval zebrafish.