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。果蝇 BMP 的玻璃底船 (Gbb) 及其受体一厢情愿 (Wit) 定义了调节神经肌肉接头 (NMJ) 突触可塑性的信号系统。 Gbb 充当逆行信号（从肌肉到支配神经元），虽然它不是神经元生存所必需的，但它对于正确的运动神经元突触发育和功能至关重要。尽管像神经生长因子这样的逆行信号早已为人所知，但负责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，允许在遗传模型生物体中研究这一过程。初步数据表明，逆行轴突运输是 BMP 信号从外周 NMJ 运输到 CNS 神经元核的机制。为了研究 BMP 信号的易位，我们将开发一种光学生物传感器，可以报告体内 BMP 通路的激活。双分子荧光互补 (BiFC)、荧光共振能量转移 (FRET) 和通路荧光标记成分（配体、受体和核胞质信使）的实时成像的组合将跟踪 BMP 信号的传输。这些研究将在细胞系和整个动物中进行，结果将通过分析分子马达的组织特异性突变体来验证。突触功效的调节是神经系统功能的一个重要过程，靶点衍生的逆行信号在这个过程中发挥着关键作用，包括最近描述的 BMP 的作用。遗传工具与高分辨率成像技术的结合将使我们能够生成并验证光学生物传感器，该传感器将普遍用于研究活样本中的 BMP 通路激活。 Wit 在果蝇神经系统中定义的通路可能在调节其他生物体的突触功效中发挥作用。了解BMP信号传输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。神经元轴突运输缺陷是许多人类神经退行性疾病（包括阿尔茨海默病和亨廷顿病）发病机制的关键因素。我们获得的有关 BMP 信号逆行轴突运输的信息将提高我们对其他信号（例如神经营养素）运输的了解，以及信号运输失调在人类神经退行性疾病发病机制中的作用的知识。