The role of spectraplakins as key integrators of axonal microtubule networks

Spectraplakins 作为轴突微管网络关键整合者的作用

• 批准号: BB/I002448/1
• 负责人: Andreas Prokop
• 金额: $ 54.91万
• 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: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI002448%2F1
• 关键词: role; spectraplakins; key; integrators; axonal

The ability of neurons to extend long processes (axons) towards other neurons, muscles or glands, is a key process underlying the formation of the neuronal networks that make up our brain and coordinate our behaviour. For example, failure of axonal growth is often fatal or causes paralysis upon spinal injury. To find cures we have to acquire a thorough understanding of the mechanisms underlying axonal growth. Growing axons follow reproducible paths signposted by chemical cues that direct the growing axon. Axonal elongation is essentially driven by filamentous skeletal elements of cells, called actin and microtubules. Actin and microtubules have to cooperate closely, and their activity must be adaptable to instructions through the guiding chemical cues. Unravelling how these different factors (actin, microtubules and signals) integrate and cross-coordinate each other during axonal growth is the key task that needs to be addressed. To this end, we focus our work on putative integrator molecules, called spectraplakins. They can physically link microtubules to actin and signalling components and, in their absence, axonal growth is severely inhibited. However, how the links of spectraplakins to actin, microtubules, and signalling components help them to perform their growth promoting function remains to be resolved. To facilitate this task, we study the spectraplakin Short stop (Shot) of fruitflies, which represents a most helpful model. Thus, Shot can be studied with powerful and rapid strategies available in fruitflies; the data obtained are relevant and can be translated into biomedical research, since the characteristics and functions of Shot are virtually identical to those of mammalian or human spectraplakins. As the starting point of our project, we have identified three regions/domains of the Shot molecule that can link Shot to microtubules, actin and, most likely, signalling factors. We have shown that all of them are absolutely required for Shot function in axonal growth. Here we will address the detail of their function, using advanced microscopy, structure-function studies, and state-of-the art technology (mass spectrometry) to identify yet unknown binding factors. As an essential further strategy we will make systematic use of combinatorial genetics. We will combine mutations of Shot with mutations in other genes known to contribute to axonal growth. The combined mutant defects will give essential insights into the functional relationships of Shot to other factors, thus mapping Shot function into the systemic context of axonal growth. Our results will provide essential new insights into the function of spectraplakins in health and disease and the regulatory networks underlying axonal growth.

神经元将长过程（轴突）扩展到其他神经元，肌肉或腺体的能力是构成我们大脑并协调我们行为的神经元网络形成的关键过程。例如，轴突生长的失败通常是致命的，或者在脊柱损伤后引起麻痹。要找到治疗方法，我们必须彻底了解轴突生长的机制。生长的轴突遵循可再现的路径，该路径通过指导生长轴突的化学线索标记。轴突伸长基本上是由称为肌动蛋白和微管的细胞的丝状骨骼元素驱动的。肌动蛋白和微管必须密切合作，并且它们的活性必须适应通过指导化学线索的指示。在轴突生长期间，这些不同的因素（肌动蛋白，微管和信号）如何相互整合和交叉坐标是需要解决的关键任务。为此，我们将工作集中在推定的集成剂分子上，称为Spectraplakins。它们可以将微管将微管与肌动蛋白和信号传导分量联系起来，并且在缺乏轴突生长的情况下，它们受到严重抑制。但是，光谱链甲蛋白与肌动蛋白，微管和信号传导成分的联系如何有助于他们执行其增长促进功能。为了促进这项任务，我们研究了Spectraplakin Shart Stop（Shot）Fruitflies，这代表了最有用的模型。因此，可以使用果蝇中的强大而快速的策略来研究射击。获得的数据是相关的，并且可以转化为生物医学研究，因为SHOT的特征和功能实际上与哺乳动物或人类Spectraplakins相同。作为我们项目的起点，我们已经确定了可以将镜头链接到微管，肌动蛋白以及最有可能的信号因子的三个区域/域。我们已经证明，所有这些都是轴突生长中射击功能绝对必需的。在这里，我们将使用先进的显微镜，结构功能研究和最先进的技术（质谱法）来解决其功能的细节，以识别但未知的结合因子。作为一个必不可少的进一步策略，我们将系统地使用组合遗传学。我们将在已知有助于轴突生长的其他基因中将射击突变与突变结合在一起。合并的突变缺陷将为镜头与其他因素的功能关系提供基本见解，从而将射击功能映射到轴突生长的系统性上下文中。我们的研究结果将为谱系在健康和疾病中的功能以及轴突增长的监管网络方面提供基本的新见解。

项目成果

Functional and Genetic Analysis of Spectraplakins in Drosophila.

• DOI: 10.1016/bs.mie.2015.06.022
• 发表时间: 2015-08
• 期刊: Methods in enzymology
• 作者: Ines Hahn;M. Ronshaugen;N. Sánchez-Soriano;A. Prokop

A new concept explaining the cell biology of axons and axon pathology

解释轴突细胞生物学和轴突病理学的新概念

• 发表时间: 2020
• 作者: Hahn, I.

A new concept explaining axonal cell biology, ageing and pathology

解释轴突细胞生物学、衰老和病理学的新概念

• 发表时间: 2021
• 作者: Hahn I

Drosophila CLIP-190 and mammalian CLIP-170 display reduced microtubule plus end association in the nervous system.

• DOI: 10.1091/mbc.e14-06-1083
• 发表时间: 2015-04-15
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Beaven R;Dzhindzhev NS;Qu Y;Hahn I;Dajas-Bailador F;Ohkura H;Prokop A
• 通讯作者: Prokop A

Spectraplakins promote microtubule-mediated axonal growth by functioning as structural microtubule-associated proteins and EB1-dependent +TIPs (tip interacting proteins).

• DOI: 10.1523/jneurosci.0416-12.2012
• 发表时间: 2012-07-04
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Alves-Silva J;Sánchez-Soriano N;Beaven R;Klein M;Parkin J;Millard TH;Bellen HJ;Venken KJ;Ballestrem C;Kammerer RA;Prokop A
• 通讯作者: Prokop A