Ultrastructure and regulation of adhesion at a genetically tractable model synapse

遗传易处理模型突触的超微结构和粘附调节

• 批准号: BB/E009085/1
• 负责人: Andreas Prokop
• 金额: $ 55.34万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE009085%2F1
• 关键词: Ultrastructure; regulation; adhesion; genetically; tractable

Behaviour, learning, memory and cognition are all outward manifestations of the complex neuronal networks that make up the nervous system. Neuronal networks are composed of nerve cells which display long projections forming reproducible points of contact with other nerve, muscle or gland cells. Electrical messages pass along these processes and are transmitted to other cells at the points of contact. Synapses are specialised structures at these contacts which carry out the information transfer. Since they can manipulate or filter information during the transfer process, synapses are key regulators of information flow in neuronal networks, essential for nervous system function and behaviour. Inappropriate function of synapses has dire consequences such as epileptic attacks, mental retardation or death. To execute their function appropriately, a number of structural features have to be correctly established when synapses form during nervous system development. They have to be established at the right places (i.e. at contacts between appropriate cells); synaptic components have to assemble precisely opposite on the signal-sending and -receiving sides of the contact; at each neuronal contact synapses have to assemble in appropriate numbers so that information transfer occurs at a strength adequate for its position in the neuronal network. So called adhesion molecules contribute essentially to all these developmental processes. Adhesion molecules sit on the surface of cells and stick to molecules on other surfaces or of material deposited in the surrounding of cells. Thus, adhesion molecules hold cells together and in certain body locations. The same is true for intercellular adhesion between neurons and their target cells at synapses. Accordingly, a number of synaptic adhesion molecules have been described, but their regulation over time and interdependencies between different classes of adhesion molecules leading to proper synapse development are hardly understood. Here we propose to focus studies of synaptic adhesion on a well known synaptic contact between nerve and muscle cells in a genetic model organism, the fruitfly Drosophila. Drosophila provides numerous advantages speeding up research into genes and their products (such as adhesion molecules). Since genes are often preserved during evolution and are similar between species as distant as humans and the fruitfly, our research will have implications for synapse-related medically relevant research. This project will make extensive use of highly sophisticated imaging techniques (electron microscopy) which allows to view cellular specialisations at extremely high resolution. Here, we will look into the detailed structures formed by adhesion molecules holding neuromuscular contacts of the fruitfly together. From such observations we can deduce, what kind of molecules are involved and whether they differ between different areas of the synaptic contact. In parallel, we will analyse potential defects of synapses in flies with inherited diseases (mutations) affecting adhesion molecules. Together with the structural descriptions, this will help us to pinpoint those molecules required at this particular synaptic contact and determine how they are arranged to carry out their function. Finally, we will try to understand how these molecules function during development in the stepwise process from the early neuromuscular contact to the final appearance and size of the functional synaptic contact.

行为、学习、记忆和认知都是构成神经系统的复杂神经元网络的外在表现。神经元网络由神经细胞组成，这些神经细胞显示长的突起，形成与其他神经、肌肉或腺细胞的可再现的接触点。电子信息沿着这些过程传递，并在接触点传递到其他细胞。突触是这些接触点上的专门结构，执行信息传递。由于它们可以在传递过程中操纵或过滤信息，因此突触是神经元网络中信息流的关键调节器，对神经系统功能和行为至关重要。不适当的突触功能有可怕的后果，如癫痫发作，智力迟钝或死亡。为了适当地执行它们的功能，在神经系统发育过程中，当突触形成时，必须正确地建立一些结构特征。它们必须建立在正确的位置（即在适当的细胞之间的接触处）;突触组件必须在接触的信号发送端和接收端精确地相对组装;在每个神经元接触处，突触必须以适当的数量组装，以便信息传递的强度足以适应其在神经元网络中的位置。所谓的粘附分子基本上有助于所有这些发育过程。粘附分子位于细胞表面并粘附到其他表面上的分子或沉积在细胞周围的材料。因此，粘附分子将细胞保持在一起并保持在某些身体位置。神经元与其靶细胞在突触处的细胞间粘附也是如此。因此，已经描述了许多突触粘附分子，但是它们随时间的调节以及导致适当突触发育的不同类别粘附分子之间的相互依赖性几乎不被理解。在这里，我们建议集中在一个众所周知的神经和肌肉细胞之间的突触接触的遗传模式生物，果蝇的突触粘附的研究。果蝇提供了许多优势，加快了对基因及其产物（如粘附分子）的研究。由于基因在进化过程中经常被保存下来，并且在人类和果蝇这样遥远的物种之间是相似的，我们的研究将对突触相关的医学研究产生影响。该项目将广泛使用高度复杂的成像技术（电子显微镜），可以以极高的分辨率观察细胞的专业化。在这里，我们将研究粘附分子将果蝇的神经肌肉接触保持在一起所形成的详细结构。从这样的观察中，我们可以推断出参与的分子类型以及它们在突触接触的不同区域之间是否不同。与此同时，我们将分析潜在的缺陷突触在苍蝇遗传性疾病（突变）影响粘附分子。与结构描述一起，这将帮助我们确定在这种特定的突触接触中所需的那些分子，并确定它们是如何排列以执行其功能的。最后，我们将试图了解这些分子在发育过程中如何发挥作用，从早期的神经肌肉接触到功能性突触接触的最终外观和大小。

项目成果

Ultrastructure and regulation of adhesion at a genetically tractable model synapse

遗传易处理模型突触的超微结构和粘附调节

• 作者: Andre Koper (Author)

Prominent Actin Fiber Arrays in Drosophila Tendon Cells Represent Architectural Elements Different from Stress Fibers

• DOI: 10.1091/mbc.e08-02-0182
• 发表时间: 2008-10-01
• 期刊: MOLECULAR BIOLOGY OF THE CELL
• 影响因子: 3.3
• 作者: Alves-Silva, Juliana;Hahn, Ines;Prokop, Andreas
• 通讯作者: Prokop, Andreas

Analysis of adhesion molecules and basement membrane contributions to synaptic adhesion at the Drosophila embryonic NMJ.

粘附分子和基底膜对果蝇胚胎NMJ上突触粘附的贡献的分析。

• DOI: 10.1371/journal.pone.0036339
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Koper A;Schenck A;Prokop A
• 通讯作者: Prokop A

Regulation of microtubule networks in neuronal growth

神经元生长中微管网络的调节

• 作者: Andreas Prokop (Author)