Trafficking of BMP signals in neurons

描述（由申请人提供）：转化生长因子-IS/骨形态发生蛋白（TGF-1 S/BMP）家族的肽在神经系统发育期间调节多种事件，并且是哺乳动物神经元功能的关键调节剂。玻璃底船（Gbb），一种果蝇BMP，及其受体Wishful thinking（Wit）定义了一个调节神经肌肉接头（NMJ）突触可塑性的信号系统。Gbb作为一种逆行信号（从肌肉到神经支配的神经元），虽然它不是神经元存活所必需的，但它对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已经被发现多年，但负责其亚细胞运输的分子机制一直难以捉摸。BMP是果蝇中逆行信号的新实例，允许在遗传模式生物中研究这一过程。初步数据表明，逆行轴突运输是BMP信号从外周的NMJ运输到CNS中的神经元核的机制。为了研究BMP信号的易位，我们将开发一种可以报告体内BMP通路激活的光学生物传感器。双分子荧光互补（BiFC）、荧光共振能量转移（FRET）和途径的荧光标记组分（配体、受体和核胞质信使）的实时成像的组合将跟随BMP信号的交通。这些研究将在细胞系和整个动物中进行，并通过分析分子马达的组织特异性突变体来验证结果。突触效能的调节是神经系统功能的一个重要过程，靶源性逆行信号在这一过程中起着关键作用，包括最近描述的BMP的作用。结合高分辨率成像技术的遗传工具的使用将使我们能够生成和验证一种光学生物传感器，该生物传感器将具有研究活体样本中BMP通路激活的通用性。在果蝇神经系统中由Wit定义的通路很可能在其他生物体中调节突触功效。了解BMP信号传递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。神经元中轴突运输的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）的发病机理中的关键因素。我们获得的信息BMP信号逆行轴突运输将提高我们的知识贩运的其他信号，如神经营养因子，和信号交通失调的作用，在人类神经退行性疾病的发病机制。

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.