Development and function of a Caenorhabditis elegans GABAergic interneuron

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate brain and dysfunction of GABAergic neurons can have profound pathological implications. I propose here to study different aspects of GABAergic neuron development and function in the model organism Caenorhabditis elegans. In C. elegans, 26 neurons express conserved GABAergic terminal differentiation markers. 25 of these are motoneurons and only one neuron, named RIS, is an interneuron which most closely resembles the dominant type of GABA neuron in vertebrates. Preliminary evidence indicates that lim-6 - a LIM homeobox transcription factor - is partly involved in RIS development, and loss of lim-6 suggests that RIS might be involved in the control of metabolism and life span. First, I will delineate cis-regulatory elements necessary for the expression of known RIS terminal differentiation markers using mutational analysis of gfp reporter genes. Second, I propose to identify the factor(s) that control RIS differentiation in association with LIM-6. I will undertake a genetic screen to identify trans-acting factors necessary for the expression of known RIS terminal differentiation markers in a lim-6 mutant background. Third, I will use transgenic animals in which RIS is genetically eliminated to determine RIS function. The proposed project will give a detailed picture of GABA neuron development and function using the C. elegans model system.