Project 1 Genetic Networks Establishing Serontonergic Neuronal Idenity

改变的5-羟色胺信号与许多神经系统和 精神障碍。这些疾病中的许多都是神经发育障碍的起源和获得这些疾病的风险 可能受到多种可遗传易感因素的影响。项目1：遗传网络 埃文·德内里斯建立了5-羟色胺能神经元的身份，并假设其中一些敏感性 因子可能是控制5-羟色胺神经元发育的基因的等位基因变体，这些等位基因可能 通过增加或减少5-羟色胺系统的活性来促进行为的发生。虽然 一些SERT变体是精神健康障碍的可识别的风险因素，大多数基因涉及 5-羟色胺神经元发育尚未被研究是否存在与疾病相关的等位基因。 这一领域尚未取得进展，因为5-羟色胺神经元很难被分子接触到 基因研究。因此，只有少数构成5-羟色胺神经元发育的基因 计划已经确定。阻碍进步的另一个关键因素是多样性 研究5-羟色胺神经元发育控制的功能需要方法学和专业知识 基因。德内里斯开发了基于转基因的工具，使人们能够直接和高度特异地获得 胚胎和成年5-羟色胺神经元。这里提出的研究将利用这些工具来 询问5-羟色胺神经元转录组，从而确定可能控制5-羟色胺神经元的基因 发展和功能。他提出的目标将解决以下问题：什么基因网络 在胚胎和出生后5-羟色胺神经元发育的关键阶段表达？什么是 吻侧和尾侧5-羟色胺神经元表达基因网络的差异？是不同阶段的 5-羟色胺神经元发育以某些基因的表达为标志？糖皮质激素有什么作用 受体(GR)在胚胎和成年5-羟色胺神经元中的作用？德内里斯希望确定一个多样化的网络 调节5-羟色胺神经元发育和功能的不同方面的fTa3受体。将这项研究整合到 ¿hearCacotnetreistCicesntoefrcapnrodjiedcatewisllergorteoantelyrgfaicimlitartkeesrstuadniedsfuanimcteiodnaltsdtuedteierms ionfinGgRththerosupgahtioctaermepfuollryalpleaxnpnredssaiondn 与P.Levitt(项目2)、R.Blakely(项目3)、E.Sanders-Bush(项目4)、D. 麦克马洪(项目6)和三个孔蒂中心核心。德内里斯的转基因系将提供新的工具 促进项目2-4和6中提出的研究。项目1的S转录组数据库将提供关键的 为研究小鼠5-羟色胺神经元转录组功能和调控提供参考信息 项目2-6。项目1的研究将使未来在经过验证的情况下筛查与疾病相关的基因变异 5-羟色胺神经元发育调控基因。

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.