Translation regulation of BDNF in brain function

描述(申请人提供)：脑源性神经营养因子(BDNF)是一个关键的参与者，通过激活TrkB受体来调控神经元的存活、分化和突触可塑性。BDNF-TrkB信号的缺失和加剧与许多人类大脑疾病有关，分别以精神障碍和癫痫为代表。我们的长期目标是阐明在正常和病理可塑性中控制BDNF产生和BDNF-TrkB功能的分子机制，这对开发治疗涉及BDNF功能障碍的疾病的新策略具有重要影响。由于BDNF的多效性，BDNF的表达受到严密的调控，以响应神经元活动的变化。尽管BDNF的转录受到复杂的调控，但它不能解释BDNF蛋白和mRNA在神经元激活时的不同时间分布，以及可扩散的BDNF蛋白是如何实现局部和突触选择性调节的。神经元活性刺激的树突运输BDNF mRNA的发现提出了一种有趣的可能性，即BDNF可能在树突/突触中局部翻译以响应神经元活动的变化，这为控制长期突触调节提供了一种新的手段。有趣的是，无论哪个启动子驱动BDNF转录，BDNF转录本的3‘端都在两个不同的多聚腺苷基化位点进行处理，产生一个短的或长的3’非翻译区(3‘UTR)。最近的研究表明，短的3‘非编码区限制神经元胞体中的BDNF mRNA，而长的3’非编码区则靶向于树突，树突状突触进而控制正常突触的发育和功能。我们的初步研究表明，神经元活动确实通过躯体和树突室中不同的3‘UTRs来调节BDNF的翻译，并发现了差异靶向BDNF3’UTRs的miRNAs。然而，控制BDNF翻译的分子机制和突触信号仍然不清楚，这是开发控制BDNF-TrkB功能的新方法的关键问题。此外，尽管我们最近的报告表明，BDNF长3‘非编码区在正常突触发育中起着重要作用，但3’非编码区对BDNF的调节如何影响癫痫的发生仍未被发现。我们推测，miRNAs对BDNF的翻译调控调控了BDNF在躯体和树突室的产生，从而调节了正常和病理可塑性。这一建议集中于以下问题：1)在躯体和树突室中控制BDNF翻译的分子机制和突触信号是什么？2)microRNAs如何参与BDNF的翻译调节以适应神经元活动的变化？3)活动依赖型BDNF翻译在癫痫发生中的功能影响是什么？ 公共卫生相关性：BDNF的准确表达对于控制正常的神经元发育和功能至关重要。脑源性神经营养因子的表达不足或恶化都可能导致脑部疾病。因此，了解脑源性神经营养因子的精确调控是制定针对许多脑部疾病的策略的关键前提。阐明BDNF在躯体和树突室的翻译对神经元活性变化的分子机制将为BDNF-TrkB功能的时空调控提供一个概念性的突破。这些研究的成功完成将极大地提高我们对BDNF翻译如何调节神经元和突触激活，进而控制正常和病理可塑性的认识。此外，这些研究将为控制神经元活性依赖的翻译的基本规则提供重要的见解，特别是通过microRNA介导的机制，这是理解脑神经元中许多mRNAs调控的一个及时而重要的问题，超出了BDNF的功能。

DESCRIPTION (provided by applicant): Brain derived neurotrophic factor (BDNF) is a key player that governs neuronal survival, differentiation and synaptic plasticity via activation of the TrkB receptor. Deficiency as well as exacerbation of BDNF-TrkB signaling is implicated in many human brain disorders, represented by mental impairment and epilepsy respectively. Our long-term goal is to elucidate molecular mechanisms that control BDNF production and BDNF-TrkB function in normal and pathological plasticity, which has important impact in developing novel strategies against diseases that involve BDNF dysfunction. Due to the pleiotropic functions of BDNF, expression of BDNF is tightly regulated in response to neuronal activity changes. Although BDNF transcription is subjected to sophisticated regulation, it could not explain the distinct temporal profiles of BDNF protein and mRNA upon neuronal activation and how the diffusible BDNF protein achieves local and synapse-selective modulation. The discovery of neuronal activity-stimulated dendritic transport of BDNF mRNA raises an intriguing possibility that BDNF may be locally translated in dendrites/synapse in response to neuronal activity changes, which offers a novel means to control long term synaptic modulation. Interestingly, regardless which promoter drives BDNF transcription, the 3'end of the BDNF transcript is processed at two alternative poly- adenylation sites, generating either a short or a long 3' untranslated region (3'UTR). The most recent studies revealed that while the short 3'UTR restricts BDNF mRNA in the neuronal soma, the long 3'UTR targets the BDNF mRNA into dendrites, which in turn governs normal synapse development and function. Our preliminary studies suggest that neuronal activity indeed regulates BDNF translation via the distinct 3'UTRs in the somatal and dendritic compartments, and identified miRNAs that differentilaly target the BDNF 3'UTRs. However, molecular mechanisms and synaptic signals controlling BDNF translation still remain elusive, which is a key issue for developing novel means to control BDNF-TrkB function. Moreover, despite the essential role of the BDNF long 3'UTR in normal synapse development as shown in our recent report, how 3'UTR-mediated regulation of BDNF may impact epileptogenesis remains uncovered. We hypothesize that translation regulation of BDNF by miRNAs governs BDNF production in the somatal and dendritic compartments to modulate normal and pathological plasticity. This proposal focuses on the following questions: 1) What are the molecular mechanisms and synaptic signals that control BDNF translation in the somatal and dendritic compartments? 2) How are microRNAs involved in translation regulation of BDNF to accommodate neuronal activity changes? 3) What are the functional impacts of activity-dependent BDNF translation in epileptogenesis? PUBLIC HEALTH RELEVANCE: Accurate expression of BDNF is crucial for governing normal neuronal development and function. Either deficiency or exacerbation of BDNF expression can contribute to brain disorders. Thus, understanding the precise regulation of BDNF is a critical prerequisite for developing strategies against many brain diseases. Elucidating molecular mechanisms that underlie BDNF translation in the somatal and dendritic compartments upon neuronal activity changes will provide a conceptual breakthrough for the spatial and temporal control of BDNF-TrkB function. Successful completion of the proposed studies will greatly advance our knowledge regarding how BDNF translation is regulated upon neuronal and synaptic activation, which in turn governs normal as well as pathological plasticity. Moreover, these studies will provide important insights for the fundamental rules that control neuronal activity-dependent translation, especially by microRNA- mediated mechanisms, a timely and important issue in understanding the regulation of many mRNAs in brain neurons, beyond BDNF function.