Altered 5HT signaling has been implicated in the pathogenesis of numerous neurological and psychiatric disorders. Many of these disorders are neurodevelopmental in origin and risk for acquiring them is likely to be influenced by multiple heritable susceptibility factors. In Project 1: Genetic Networks Establishing Serotonergic Neuronal Identity, Evan Deneris hypothesizes that some of these susceptibility factors may be allelic variants of genes that govern 5HT neuron development and that these alleles may contribute to behavioral pathogenesis by adversely increasing or decreasing 5HT system activity. Although some SERT variants are identifiable risk factors for mental health disorders, the majority of genes involved in 5HT neuron development have not yet been investigated for the presence of disease-associated alleles. Advances in this area have not been made because 5HT neurons are difficult to access for molecular genetic studies. Consequently, only a small number of genes that compose the 5HT neuron developmental program have been identified. An additional critical factor that has hindered progress is that diverse methodology and expertise is required to investigate the function of 5HT neuron developmental control genes. Deneris has developed transgenic-based tools that enable direct and highly specific access to embryonic and adult 5HT neurons. The research proposed here will take advantage of these tools to interrogate the 5HT neuron transcriptome and thereby identify genes that may control 5HT neuron development and function. His proposed aims will address the following questions: What network of genes is expressed during critical stages of embryonic and postnatal 5HT neuron development? What are the differences between the rostral and caudal 5HT neuron expressed gene networks? Are different stages of 5HT neuron development marked by expression of certain sets of genes? What role does the glucocorticoid receptor (GR) play in embryonic and adult 5HT neurons? Deneris expects to identify a diverse network of fTa3ctors that govern different facets of 5HT neuron development and function. Integration of this research into ?hearCacotnetreistCicesntoefrcapnrodjiedcatewisllergorteoantelyrgfaicimlitartkeesrstuadniedsfuanimcteiodnaltsdtuedteierms ionfinGgRththerosupgahtioctaermepfuollryalpleaxnpnredssaiondn orchestrated collaborations with P. Levitt (Project 2), R. Blakely (Project 3), E. Sanders-Bush (Project 4), D. McMahon (Project 6) and the three Conte Center Cores. Deneris'transgenic lines will provide new tools to facilitate studies proposed in Projects 2-4 and 6. Project 1's transcriptome databases will provide critical reference information for studies of mouse 5HT neuron transcriptome function and regulation proposed in Projects 2-6. Project 1 studies will enable future screens for disease relevant genetic variants in validated 5HT neuron developmental control genes.
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