Distinct roles of somatically and dendritically synthesized BDNF in spine morphog

体细胞和树突状合成的 BDNF 在脊柱形态中的不同作用

• 批准号: 8679016
• 负责人: BAOJI XU
• 金额: $ 40.93万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679016
• 关键词: 3' Untranslated Regions; Actins; Action Potentials; Animal Model; Binding; Brain; Brain-Derived Neurotrophic Factor; Dendrites; Dendritic Spines; Development; Excitatory Synapse; Functional RNA; Genes; Goals; Guanine Nucleotide Exchange Factors; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Knock-in Mouse; Label; Learning; Location; Mediating; Memory; Mental Retardation; Messenger RNA; Mitogen-Activated Protein Kinases; Molecular; Morphogenesis; Morphology; Mus; NGFR Protein; Neurodegenerative Disorders; Neurons; Pathway interactions; Phase; Phosphoinositide Pathway; Phosphotransferases; Physiological; Play; Process; Proteins; Rattus; Research Project Grants; Role; Shapes; Signal Transduction; Signaling Molecule; Single Nucleotide Polymorphism; Sorting - Cell Movement; Stimulus; Structure; Synapses; Synaptic plasticity; System; Testing; Tetrodotoxin; Translations; Vertebral column; Whole-Cell Recordings; density; gene function; immunocytochemistry; in vivo; inhibitor/antagonist; insight; knock-down; mutant; nervous system disorder; neuronal cell body; novel; receptor; response; small hairpin RNA

DESCRIPTION (provided by applicant): The vast majority of excitatory synapses occur on spines, which are dynamic structures that undergo changes in size, shape, and number during development and in response to physiological stimuli such as neuronal activity and learning. The overall goal of this research project is to elucidate the molecular mechanisms that regulate dendritic spine morphogenesis. Spine development includes formation, maturation, and pruning. Although many proteins have been found to be important for spine formation, the molecular pathway controlling spine formation is not fully understood. Even less is known about the molecular mechanism regulating the later phases of spine development, especially spine pruning, which is an activity-dependent process and likely plays an important role in the refinement of synaptic connections. The gene for brain-derived neurotrophic factor (BDNF) produces two pools of mRNA, with either a short or long 3' untranslated region (3'UTR). Our recent findings show that short 3'UTR Bdnf mRNA is restricted to the soma, whereas long 3'UTR Bdnf mRNA is also transported to dendrites for local translation. This application is aimed at testing the hypothesis that BDNF synthesized in the soma and dendrites regulates formation, maturation, and pruning of spines via distinct signaling cascades and that single nucleotide polymorphisms (SNP) in the human Bdnf 3'UTR may impair localization and translation of Bdnf mRNA in dendrites, leading to spine dysmorphogenesis and cognitive impairments. These hypotheses will be tested in three specific aims. Specific aim 1 proposes to examine the distinct roles of somatically and dendritically synthesized BDNF in spine morphogenesis in cultured rat hippocampal neurons. Specific aim 2 proposes to elucidate the signaling cascades mediating the effects of BDNF on the formation, maturation, and pruning of spines. Specific aim 3 proposes to determine the effects of a human SNP in the long Bdnf 3'UTR on spine morphogenesis and synaptic plasticity. Findings from these studies likely reveal novel mechanisms governing gene function and spine morphogenesis, and provide insights into the functional consequence of SNPs in non-coding sequences.

描述（由申请人提供）：绝大多数兴奋性突触发生在棘上，棘是动态结构，在发育过程中以及响应生理刺激（如神经元活动和学习）而发生大小、形状和数量的变化。本研究项目的总体目标是阐明调节树突棘形态发生的分子机制。脊柱发育包括形成、成熟和修剪。虽然已经发现许多蛋白质对棘的形成很重要，但控制棘形成的分子途径尚未完全了解。关于调控棘发育后期的分子机制，特别是棘修剪，所知更少，这是一个依赖于活动的过程，可能在突触连接的细化中起着重要作用。脑源性神经营养因子（BDNF）基因产生两个mRNA库，具有短或长的3'非翻译区（3'UTR）。我们最近的研究结果表明，短的3 'UTR Bdnf mRNA仅限于索马，而长的3' UTR Bdnf mRNA也被转运到树突进行局部翻译。本申请旨在检验以下假设：在索马和树突中合成的BDNF通过不同的信号级联调节棘的形成、成熟和修剪，并且人BDNF 3 'UTR中的单核苷酸多态性（SNP）可能损害树突中BDNF mRNA的定位和翻译，导致棘形态发育异常和认知障碍。这些假设将在三个具体目标中得到检验。具体目标1提出了研究不同的作用，体细胞和树突合成的BDNF在脊髓形态发生在培养的大鼠海马神经元。具体目标2提出阐明介导BDNF对棘的形成、成熟和修剪的影响的信号级联。具体目标3提出确定长Bdnf 3'UTR中的人SNP对棘形态发生和突触可塑性的影响。这些研究的结果可能揭示了基因功能和脊柱形态发生的新机制，并提供了非编码序列中SNP的功能后果的见解。