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

描述(申请人提供)：本申请建议继续研究控制5-羟色胺(5-羟色胺)神经递质特征和5-羟色胺调节行为发展的转录机制。改变的5-羟色胺信号与许多神经和精神疾病的发病机制有关，如自闭症、婴儿猝死综合征、抑郁症和焦虑症。这些疾病中的许多起源于神经发育，获得这些疾病的风险受到可遗传易感因素的影响。因此，刺激这项研究的总体概念是，控制5HT神经元发育的转录程序中的基因驱动变异通过不利改变5HT系统的活动而导致某些神经和精神疾病的发病。本研究的重点是Pet-1ETS因子，该因子在5HT出现之前特异性地在有丝分裂后的5HT神经元前体细胞中开始表达，然后在所有成年5HT神经元中维持表达。在小鼠的功能丧失研究表明，Pet-1是5-羟色胺神经元表型和5-羟色胺调节行为的关键转录决定因素。这些发现支持依赖Pet-1的转录程序的存在，该程序通过控制胚胎5HT神经元的发育来影响5HT调节的行为。这里提出的新目标将解决以下问题：1)FEV ETS因子是人类Pet-1的同源基因吗？FEV依赖的遗传程序是否控制人类5HT神经元的发育？2)Pet-1/FEV活性水平是否决定5HT神经元递质特性和5HT神经元功能的水平？3)Pet-1在成熟的5HT神经元中扮演什么角色？4)Pet-1和FEV的转录调控是保守的吗？提出的目标将用分子遗传学方法进行研究，我们新开发的基于遗传的工具将极大地促进我们在活体内访问5HT神经元。如果FEV在人类5-羟色胺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疾病以及行为个体间差异的潜在风险来源。拟议的研究可能会对分子精神病学研究产生长期影响，因为它促进了对支配5HT神经元发育的遗传机制的理解，并确定了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.