Genetic dissection of baseline and stress-induced serotonin biosynthesis in Caenorhabditis elegans ADF chemosensory neurons

Abstract

This thesis presents a genetic analysis of three independent regulatory programs that govern serotonin biosynthesis enzyme tph-1 gene expression in a pair of serotonergic chemosensory neuron ADF in the nematode Caenorhabditis elegans, including the molecular pathway that defines baseline tph-1expression at favorable environment, and the molecular pathways that upregulate tph-1 gene expression under two stress paradigms including pathogenic infection and dauer formation.;Continued tph-1 gene expression and baseline 5-HT neurotransmission in ADF chemosensory neurons at favorable environment coordinates multiple innate behaviors in C. elegans. This steady state 5-HT biosynthesis is not a default serotonergic cell fate, but is programmed in a cell-specific manner by GPB-1/Gbeta subunit to OCR-2/OSM-9 TRPV channel signaling. Disruption of Gbeta-mediated signaling by genetic mutation of gpb-1 gene abrogates tph-1 expression in ADF neurons at favorable environment. The Goalpha GOA-1 serves as a negative regulator of the GPB-1-OCR-2/OSM-9 pathway.;tph-1 gene expression and 5-HT level in ADF neurons can be significantly enhanced during pathogenic infection by certain bacterial species to facilitate aversive learning and pathogen-avoidance behavior. This level of regulation requires activation of a conserved TIR-1/MAPK innate immune pathway expressed in the ADF neurons by infection-related cues. Two types of cellular damage commonly associated with infection -- protein translational inhibition and mitochondria) dysfunction in the intestine and hypodermis robustly induce tph-1 gene upregulation in ADF neurons, mimicking the effect of pathogen infection, suggesting that serotonergic neurons may recognize pathogen-induced damage signals as aversive cues during infection.;Dauer formation is an internal physiological stress that induces tph-1 gene upregulation in ADF neurons. This layer of regulation requires remodeling of ADF sensory cilia architecture by a Hedgehog receptor Patched-related gene daf-6 expressed in surrounding amphid glial cells during dauer formation. From a candidate RNAi screen, the Hedgehog-related protein WRT-6 was identified as another regulator of ADF tph-1 expression. WRT-6 is expressed in amphid socket glia and may serve as a potential ligand for DAF-6.