Activity-dependent translation and release of BDNF

BDNF 的活动依赖性翻译和释放

• 批准号: 8299681
• 负责人: James Q Zheng
• 金额: $ 21.67万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299681
• 关键词: 3' Untranslated Regions; Address; Affinity; Brain; Brain Diseases; Brain-Derived Neurotrophic Factor; Chimeric Proteins; Defect; Dendrites; Dendritic Spines; Development; Docking; Epileptogenesis; Event; Family; Fluorescence; Fluorescence Microscopy; Generations; Glutamates; Hippocampal Mossy Fibers; Hippocampus (Brain); Image; Lead; Learning; Life; Location; Mediating; Memory impairment; Mental Depression; Mental disorders; Messenger RNA; Modification; Molecular; Nervous system structure; Neurons; PHluorin; Pattern; Play; Polyadenylation; Process; Production; Proteins; Public Health; Receptor Protein-Tyrosine Kinases; Regulation; Reporter; Resolution; Rest; Role; Signal Transduction; Site; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Time; Transcript; Translating; Translations; Untranslated Regions; Validation; Vertebral column; Vesicle; cellular imaging; member; molecular imaging; neuronal cell body; neuronal circuitry; neuronal survival; neurotrophic factor; novel; postsynaptic; reconstruction; research study; response; spatiotemporal; trafficking; two-photon

DESCRIPTION (provided by applicant): Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays fundamental roles in neuronal survival, differentiation, circuitr formation/reconstruction, and synaptic plasticity. Deficiency in BDNF functions has been implicated in psychiatric disorders, depression, and learning-memory deficits. BDNF actions on neuronal circuitry are circuitry- and synapse-selective actions, implicating a potential involvement of localized expression/release of BDNF proteins. The primary BDNF transcript is processed at two alternative polyadenylation sites, giving rise to two pools of BDNF mRNAs harboring a short and a long 3'UTR of 0.35 kb and 2.85 kb but encoding the same BDNF protein. The long 3'UTR contains additional distinct sequence entities, which offer specific posttranscriptional regulation of BDNF. BDNF mRNA bearing the short 3'UTR is restricted in the cell body whereas that bearing long 3'UTR is present in the dendritic region. Importantly, the long 3'UTR is responsible for dendritic targeting of BDNF mRNA, which is enhanced by neuronal activity. Furthermore, the long 3'UTR was found to repress BDNF translation in resting neurons but undergoes activity-dependent BDNF translation in dendrites. Loss of the BDNF long 3'UTR results in defects in dendritic spine development and plasticity, indicating an important role for dendritic expression of BDNF through the long transcripts. We hypothesize that the long 3'UTR BDNF mRNA may mediate translation of BDNF in selective dendritic regions in response to local synaptic activities, leading to spatiotemporally restricted BDNF release for synapse-specific modification of synapses. This proposed study will evaluate this exciting hypothesis and address several crucial issues concerning BDNF generated from the long 3'UTR transcripts. Of most importance is whether BDNF protein is locally produced from long 3'UTR transcripts by synaptic activity, packed into vesicles, and released from stimulated synapses. It is also important to know if BDNF proteins translated from the short and long transcripts behave differentially in terms of their distribution, trafficking, and release in respose to local synaptic activity. Advanced live cell imaging will be performed to address three specific questions: (1) whether the long 3'UTR BDNF transcripts mediate activity-dependent localized translation of BDNF; (2) whether BDNF proteins synthesized from the long 3'UTR transcripts are packed in vesicles, and can localize to the site of synaptic activities; (3) whether BDNF proteins synthesized from the long 3'UTR transcripts can actually be released in response to synaptic activities. Answers to these questions will provide the support to a novel mechanism concerning BDNF production, trafficking, and secretion that may play an important role in synaptic modifications. Results from this study could have a major impact on our understanding of the molecular and cellular mechanisms underlying BDNF functions in normal and disease brains. PUBLIC HEALTH RELEVANCE: Brain derived neurotrophic factor (BDNF) plays a crucial role in brain development and functions but is produced from two pools of BDNF mRNAs harboring a short and a long 3'UTR. This study will evaluate if the long 3'UTR BDNF mRNA mediate local translation and release of BDNF for synaptic modification. Results from this study could have a major impact on our understanding of BDNF functions in normal and disease brains, thus having direct relevance to public health.

描述（由申请人提供）：脑衍生的神经营养因子（BDNF），神经营养蛋白家族的成员，在神经元存活，分化，电路形成/重建和突触可塑性中扮演着基本角色。 BDNF功能的缺陷与精神疾病，抑郁症和学习记忆缺陷有关。 BDNF对神经元电路的作用是回路和突触选择性作用，暗示了BDNF蛋白的局部表达/释放的潜在参与。主要的BDNF转录本在两个替代的聚腺苷酸位点进行处理，从而产生两个bdnf mRNA池，其中含有短而长的3'UTR为0.35 kb和2.85 kb，但编码相同的BDNF蛋白质。长3'UTR包含其他不同的序列实体，这些实体提供了BDNF的特定转录后调节。带有短3'UTR的BDNF mRNA在细胞体中受到限制，而在树突区域中存在长3'UTR。重要的是，长3'UTR负责BDNF mRNA的树突状靶向，这通过神经元活性增强。此外，发现长3'UTR在静息神经元中抑制BDNF翻译，但在树突中进行了依赖活性的BDNF翻译。 BDNF长3'UTR的丧失导致树突状脊柱发育和可塑性缺陷，这表明通过长转录本通过长转录物的树突状表达具有重要作用。我们假设长3'UTR BDNF mRNA可以响应局部突触活性，在选择性树突状区域中介导BDNF的翻译，从而导致时空限制的BDNF BDNF释放，以释放突触的突触特异性修饰。这项提出的研究将评估这一令人兴奋的假设，并解决有关长3'UTR转录本产生的BDNF的几个关键问题。最重要的是，BDNF蛋白是否是通过长3'UTR转录本局部产生的，该蛋白是通过突触活性，包装成囊泡并从刺激的突触中释放出来的。同样重要的是要知道BDNF蛋白是否从简短和长的笔录中翻译而成，其分布，贩运和对局部突触活动的重新释放而言。先进的活细胞成像将进行以解决三个特定问题：（1）长3'UTR BDNF转录本是否介导BDNF的活动依赖性局部翻译； （2）是否将长3'UTR转录本合成的BDNF蛋白包装在囊泡中，并且可以定位于突触活动的位点； （3）实际上可以释放从长3'UTR转录本合成的BDNF蛋白来响应突触活动。这些问题的答案将为有关BDNF生产，贩运和分泌的新型机制提供支持，该机制可能在突触修饰中起重要作用。这项研究的结果可能会对我们对正常和疾病大脑中BDNF功能的分子和细胞机制的理解产生重大影响。 公共卫生相关性：脑衍生的神经营养因子（BDNF）在大脑发育和功能中起着至关重要的作用，但是由两个具有短且长3'UTR的BDNF mRNA池产生的。这项研究将评估长3'UTR BDNF mRNA是否介导BDNF的局部翻译和释放进行突触修饰。这项研究的结果可能会对我们对正常和疾病大脑中BDNF功能的理解产生重大影响，从而与公共卫生有直接相关。