morphology, connect with correct synaptic partners, and choose their neurotransmitters are fundamental questions for understanding the formation and function of a nervous system. The complexity and difficulty in accessibility to individual neurons in higher organisms are major experimental obstacles for elucidating such mechanisms. The simple nervous system of the nematode C. elegans is well characterized anatomically and offers an excellent experimental model to address each event of neuronal connection formation in vivo with single cell resolution. The investigator has identified unc-30, a homeodomain protein, as the key regulator in controlling the terminal differentiation of 19 GABAergic neurons. Loss of unc-30 function causes these neurons to fail to differentiate properly and to lack GABA; ectopic expression of unc-30 transforms other cells into GABAergic neurons. To identify other genes that function in these neurons' differentiation, the applicant has studied unc-25, a potential target gene of unc-30, that encodes glutamic acid decarboxylase (GAD) and is responsible for producing GABA in these neurons. This work is the only example among multicellular organisms that GAD is defined genetically and a regulator of GAD is identified. The main aim of this proposal is to dissect the complete molecular genetic program of the terminal differentiation of these GABAergic neurons. Several approaches will be used to identify genes involved in this process, such as isolation of suppressors of gain-of-function mutants of unc-30 and dominant enhancers of a weak allele of unc-30, and isolation of differentially expressed mRNAs. A number of reagents and mutants have already been identified to help analyze in depth the function of these genes. The proposal also includes analysis of how other types of GABAergic neurons in C. elegans are specified. GABA is the major inhibitory neurotransmitter in all animals. Abnormal GABAergic neuron function has been implicated in several human diseases. This work may provide insights to the understanding of basic mechanisms underlying the precision of neuronal connections and diversification of neuronal types in all organisms.
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