DESCRIPTION (provided by applicant): During the terminal differentiation, every neuron must choose a transmitter. Many different neurons choose the same transmitter, thus the same neurotransmitter may subserve many different functions. Although factors regulating early stages of neurogenesis are beginning to be elucidated, the genetic network determining neurotransmitter phenotypes is largely unknown.This proposal uses genetic approaches to identify genes determining the serotonergic phenotype and to study the role of serotonergic neurons in metabolic control in C. elegans. The proposed experiments take advantages that serotonin-deficient worms are fully viable, and the serotonergic system, including 5 classes, a total of 9 neurons, offers both the simplicity and diversity for genetic and physiological analysis.First, we will identify genes regulating serotonergic neuron development. We have isolated 2 classes of mutations affecting the development of particular serotonergic neurons. We will assess if the mutations prevent the neuron generation, or if they affect particular aspects of the final neuronal identity. We will clone 2-3 genes likely acting in the terminal differentiation and determine their expression pattern. Second, we will determine if there are cell-specific regulators directing serotonin synthesis. Through molecular dissection of the promoter of the serotonin synthetic enzyme gene tph-1, we will determine if discrete sequence motifs direct tph-1 expression in particular neurons. We will test if the POU-transcription factor UNC-86 that is required for tph-1 expression in a subset of the serotonergic neurons directly regulates tph-1. Third, we will assess the role of serotonergic neurons in metabolic control. Our previous study indicated that serotonin regulates the TGF-b and insulin neuroendocrine pathways to modulate C. elegans metabolism. We will test if mutations affecting particular serotonergic neurons affect a specific metabolic regulatory pathway, and if restoration of serotonin production in particular neurons rescues the metabolic defects of serotonin deficient mutants. Fourth, We will use genetic epistasis analysis to assess the interaction of serotonin and other neural signaling that also regulate metabolism. The goal is to explore how serotonin signals are integrated to modulate metabolism.Dysregulations of serotonin signaling have been associated with eating disorders, type II diabetes, and obesity. Identification of genes that determine the serotonergic phenotype and understanding the role of serotonergic neurons in the regulation of metabolism in C. elegans will provide reagents to study the development and function of serotonergic neurons in human.
|Effective start/end date||12/1/01 → 11/30/12|