Function of the Pet-1 ETS factor in the mammalian 5-HT system

描述（由申请人提供）：本申请建议继续研究控制5-羟色胺（5 ht）神经元递质性状和5 ht调节行为发育的转录机制。改变的5 ht信号转导已经涉及许多神经和精神疾病的发病机制，例如自闭症、婴儿猝死综合征（SIDS）、抑郁症和焦虑症。其中许多疾病起源于神经发育，其患病风险受到遗传易感因素的影响。因此，一般的概念，刺激这里提出的研究是，基因驱动的变化，在转录程序管理5 HT神经元的发展有助于某些神经和精神疾病的发病机制，不利地改变5 HT系统的活动。建议的研究重点是Pet-1 ETS因子，其表达在有丝分裂后的5 HT神经元前体细胞中特异性地启动，然后在所有成年5 HT神经元中维持。在小鼠中的功能丧失研究表明，Pet-1是5 ht神经元表型和5 ht调节行为的关键转录决定因子。这些发现支持了Pet-1依赖性转录程序的存在，该程序通过其对胚胎5 ht神经元发育的控制来影响5 ht调节的行为。本文提出的新目标将解决以下问题：1）FEV ETS因子是Pet-1的功能性人类直系同源物吗？FEV依赖性遗传程序是否控制人类5 ht神经元发育？2)Pet- 1/FEV活性水平是否决定了5 HT神经元递质特性和5 HT神经元功能的水平？3)Pet-1在成熟的5 HT神经元中起什么作用？4)Pet-1和FEV的转录调控是否保守？所提出的目标将与分子遗传学方法进行研究，并将大大促进我们新开发的遗传为基础的工具，旨在访问5 HT神经元，在体内。如果FEV在人类5 HT神经元发育中起作用，那么由遗传或环境因素引起的FEV活性的改变是精神或神经系统疾病和行为个体间变异的潜在风险来源。拟议的研究可能会对分子精神病学研究产生长期影响，因为它促进了对控制5 ht神经元发育的遗传机制的理解，并确定这些机制如何影响行为和生理。

DESCRIPTION (provided by applicant): This application proposes to continue research into the transcriptional mechanisms that control development of serotonin (5ht) neuron transmitter traits and 5ht-modulated behaviors. Altered 5ht signaling has been implicated in the pathogenesis of numerous neurological and psychiatric disorders such as autism, sudden infant death syndrome (SIDS), depression, and anxiety. Many of these disorders are neurodevelopmental in origin and risk for acquiring them is influenced by heritable susceptibility factors. Thus, the general concept that stimulates the research proposed here is that genetically driven variation in transcriptional programs governing 5ht neuron development contributes to the pathogenesis of certain neurological and psychiatric disorders by adversely altering 5ht system activity. The focus of the proposed research is the Pet-1 ETS factor whose expression is initiated specifically in postmitotic 5ht neuron precursors before the appearance of 5ht and then maintained in all adult 5ht neurons. Loss of functions studies in the mouse demonstrated that Pet-1 is a critical transcriptional determinant of 5ht neuron phenotype and 5ht-modulated behaviors. These findings support the existence of a Pet-1 dependent transcriptional program that impacts 5ht- modulated behaviors through its control of embryonic 5ht neuron development. The new aims proposed here will address the following questions: 1) Is the FEV ETS factor the functional human orthologue of Pet-1 and does a FEV-dependent genetic program govern human 5ht neuron development? 2) Does the level of Pet- 1/FEV activity determine the level of 5ht neuron transmitter traits and 5ht neuron function? 3) What role does Pet-1 play in mature 5ht neurons? 4) Is the transcriptional control of Pet-1 and FEV conserved? The proposed aims will be investigated with molecular genetic approaches and will be greatly facilitated by our newly developed genetic based tools designed to access 5ht neurons, in vivo. If FEV functions in human 5ht neuron development then alterations in FEV activity brought about either by genetic or environmental factors are a potential source of risk for psychiatric or neurological disease and interindividual variation in behavior. The proposed studies are likely to have a long-term impact on molecular psychiatry research by advancing an understanding of the genetic mechanisms that govern 5ht neuron development and determining how these mechanisms impact behavior and physiology.