Trafficking of BMP signals in neurons

BMP 信号在神经元中的运输

• 批准号: 7099772
• 负责人: GUILLERMO MARQUES
• 金额: $ 16.37万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-06 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099772
• 关键词: Drosophilidae; genetics; ligands; motor neurons; mutant; neuronal transport; neurons; receptor; role; tissues

DESCRIPTION (provided by applicant): Peptides of the Transforming Growth Factor-IS/Bone Morphogenetic Protein (TGF-IS/BMP) family regulate multiple events during development of the nervous system and are key modulators of neuronal function in mammals. Glass bottom boat (Gbb), a Drosophila BMP, and its receptor Wishful thinking (Wit) define a signaling system that regulates synaptic plasticity at the neuromuscular junction (NMJ). Gbb acts as a retrograde signal (from muscle to innervating neuron), and while it is not required for neuron survival, it is essential for proper motoneuron synaptic development and function. Although retrograde signals like Nerve Growth Factor have been known for years, the molecular mechanisms responsible for their subcellular trafficking have been elusive. BMP's are new instances of retrograde signaling in Drosophila, allowing the study of this process in a genetic model organism. Preliminary data suggest that retrograde axonal transport is the mechanism for BMP signal trafficking from the NMJ in the periphery to the neuron nucleus in the CNS. To investigate the translocation of the BMP signal we will develop an optical biosensor that can report BMP pathway activation in vivo. A combination of Bimolecular Fluorescence Complementation, (BiFC), Fluorescence Resonance Energy Transfer (FRET) and live imaging of the fluorescently tagged components of the pathway (ligands, receptors and nucleocytosolic messengers) will follow the traffic of the BMP signal. These studies will be performed in cell lines and in whole animals, and the results will be verified by analysis of tissue-specific mutants of molecular motors. Modulation of synaptic efficacy is an essential process in nervous system function, and target-derived retrograde signals play a key role in this process, including the recently described role of BMPs. The use of genetic tools in combination with high resolution imaging techniques will allow us to generate and validate an optical biosensor that will be of general utility to study BMP pathway activation in live samples. The pathway defined by Wit in the fly nervous system is likely to be at work in regulation of synaptic efficacy in other organisms. Learning the mechanism of BMP signal transport will have a major impact in our understanding of the regulation of synaptic growth and synaptic plasticity. Defects In axonal transport in neurons are critical factors in the pathogenesis of a number of human neurodegenerative disorders, including Alzheimer's and Huntington's diseases. The information we obtain about BMP signal retrograde axonal transport will improve our knowledge of the trafficking of other signals, such as neurotrophins, and of the role of the disregulation of signal traffic in the pathogenesis of human neurodegenerative disease.

描述（由申请人提供）：转化生长因子-IS/骨形态发生蛋白（TGF-IS/BMP）家族的肽调节神经系统发育过程中的多个事件，并且是哺乳动物神经元功能的关键调节剂。玻璃底船（GBB），果蝇BMP及其受体一厢情愿（机智）定义了一个信号系统，该信号系统调节神经肌肉连接处的突触可塑性（NMJ）。 GBB充当逆行信号（从肌肉到神经神经元），虽然神经元存活不需要它，但对于适当的运动神经元突触发育和功能至关重要。尽管逆行信号（如神经生长因子）已知多年了，但导致其亚细胞运输的分子机制一直难以捉摸。 BMP是果蝇中逆行信号传导的新实例，可以在遗传模型生物体中研究该过程。初步数据表明，逆行轴突转运是BMP信号运输从周围NMJ到中枢神经系统神经元核的机制。为了研究BMP信号的易位，我们将开发一种可以在体内报告BMP途径激活的光学生物传感器。双分子荧光互补，（BIFC），荧光谐振能传递（FRET）和荧光标记的途径标记成分的实时成像（配体，受体和核细胞质体的启动器）的结合将跟随BMP信号的流量。这些研究将在细胞系和整个动物中进行，并通过分析分子电动机的组织特异性突变体来验证结果。突触功效的调节是神经系统功能的重要过程，目标衍生的逆行信号在此过程中起关键作用，包括最近描述的BMP的作用。遗传工具与高分辨率成像技术结合使用将使我们能够生成和验证一种光学生物传感器，该光学生物传感器将是研究实时样品中BMP途径激活的一般实用性。蝇神经系统中的机智定义的途径可能在调节其他生物的突触功效方面起作用。学习BMP信号转运的机制将对我们理解突触生长和突触可塑性的调节产生重大影响。神经元中轴突转运的缺陷是许多人类神经退行性疾病的发病机理的关键因素，包括阿尔茨海默氏症和亨廷顿疾病。我们获得的有关BMP信号逆行轴突运输的信息将改善我们对其他信号的运输的了解，例如神经营养蛋白，以及疏离信号流量在人类神经退行性疾病的发病机理中的作用。