This application proposes a unique avenue of research aimed at the development and function of the mammalian serotonin neurotransmitter system. The research is based on our discovery of a novel ETS domain transcription factor, Pet-1, whose expression precisely marks 5-HT neurons before 5-HT appears in the hindbrain and before 5-HT neurons have begun to migrate to their adult midbrain/hindbrain positions. The discovery of a transcription fact that is specifically expressed in the mammalian 5-HT system is unprecedented. It serotonergic-specific expression pattern together with the presence of a Pet-1 DNA binding sites in human and mouse genes, which in large part defines the differentiated phenotype of 5-HI neurons, suggest that Pet-1 is a key determinant in the decision to become a 5-HT neuron. The experiments described in this application are aimed at testing this hypothesis and to exploit the provocative expression pattern of Pet-1 to control heterologous gene expression in a serotonergic-specific manner. The proposed aims are: 1) Investigate expression of Pet-1 alternative forms and expression of other ETS factors in the 5-HT system. 2) Identify a Pet genomic DNA fragment capable of controlling serotonergic-specific gene expression. 3) Investigate the transcriptional interaction of Pet-1 with the serotonin transporter (5-HTT), 5 HT1a receptor and tryptophan hydroxlase (TPH) genes. 4) Create a Pet-1 loss of function mouse and determine its phenotype. The function of the central 5-HT system is abnormal in numerous psychiatric disorders and thus this system is the target of several highly effective pharmacological agents that are used to treat these disorders. The information gained from completion of the proposed aims is likely to have significant impact on our basic understanding of the 5-HT system and may lead in the future to the creation of novel animal models for psychiatric disorders involving the 5-HT system.
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