Uncovering the role of the ESCRT machinery in neuron pruning

揭示 ESRT 机制在神经元修剪中的作用

• 批准号: BB/L022672/1
• 负责人: Darren Williams
• 金额: $ 59.79万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL022672%2F1
• 关键词: Uncovering; role; ESCRT; machinery; neuron

Like a computer or any other complex electronic device our brain needs to be accurately 'wired together' to function properly. Current thinking suggests that disruptions in wiring may underlie a number of psychiatric disorders, so to understand how wiring in the nervous system goes wrong is very important for aiding therapeutic approaches for such disorders. As such this work is likely to contribute to the healthcare sector and thus to our society. As the nervous system forms, nerve cells grow to make connections with one another and as such are like the wires of an electrical device. When nerve cells grow, they do so in an exuberant manner, often generating many extension branches. Some of these branches enter the wrong territory or are redundant and need to be removed. We call this removal of branches 'pruning'. Pruning of excess or redundant branches is important for adjusting the nervous system so that it can work with precision. In many cases pruning happens by branches being cut off, hence the term 'pruning'. Although we know a great deal about how the nervous system develops, our understanding of how branches are physically cut away remains a mystery. We have been using the fruitfly Drosophila to try and answer this question. We use flies because they share most of their genes with humans, so what we learn in the fly can be easily translated to humans. At the same time, fruitflies have a relatively simple nervous system that is more accessible and easier to study than more complex nervous systems as found in mouse. Flies are perfect for applying genetics to investigate their biology. For example, fruitflies grow quickly so one can do genetic screens; ie. breaking genes, which is a powerful way uncovering how things work. In this project we are focusing on pruning in the nervous system. Here, the fly provides a great opportunity, as many of its nerve cells are recycled during metamorphosis, when a maggot turns into a fly. Pruning is important for the recycling process. We study how nerve cells undergo pruning by using fluorescent 'glowing' genes from a jellyfish, which allows us to see nerve cells inside the living animal. Using these glowing nerve cells and fly genetics we found that a family of proteins called the Endosomal Sorting Complexes Required for Transport (ESCRT) are important for pruning. These ESCRT proteins assemble and together form a machine that cuts cell membranes. Because cells are really a large system of membranes containing different components, this group of proteins is important and used for many different processes in different parts of cells e.g. they are also used when cells divide in two. To schedule these proteins for each specific task, they have very specific adaptors that direct them to work in the right place at the right time. We think that something like the cutting that occurs when a cell divides is also happening during nerve cell branch pruning. We are the first people to have any evidence to suggest that the ESCRT machinery is involved in cutting nerve cell branches. Because this observation gives us a new clue as to the genes and mechanisms that regulate pruning in the nervous system, this is a very important observation. We would now like to confirm these observations and extend them. We want to know which of the ESCRT family members are important for pruning and which are not; how these machines assemble, whether they are actually needed directly at the place where the branch is cut and how the cutting process is controlled by the adaptors. We hope our work will resolve part of this mystery and that in future the new insights that our work can help up understand what happens when wiring goes wrong in human disorders of the nervous system, and, by extension what therapeutic approaches could be developed to correct such defects or lessen their impact on mental health and well being.

就像计算机或任何其他复杂的电子设备一样，我们的大脑需要精确地“连接在一起”才能正常工作。目前的想法表明，布线中断可能是许多精神疾病的基础，因此了解神经系统中的布线如何出错对于帮助治疗此类疾病非常重要。因此，这项工作很可能有助于医疗保健部门，从而为我们的社会。 随着神经系统的形成，神经细胞生长以相互连接，就像电气设备的电线一样。当神经细胞生长时，它们以旺盛的方式生长，通常产生许多延伸分支。其中一些分支进入了错误的领域，或者是多余的，需要删除。我们把这种修剪树枝的行为称为“修剪”。修剪多余或多余的树枝对于调整神经系统非常重要，这样它就可以精确地工作。在许多情况下，修剪发生的树枝被切断，因此术语“修剪”。虽然我们对神经系统的发育过程有很多了解，但我们对分支是如何被物理切断的理解仍然是一个谜。 我们一直在用果蝇来尝试回答这个问题。我们使用苍蝇是因为它们与人类共享大部分基因，所以我们在苍蝇身上学到的东西可以很容易地翻译给人类。与此同时，果蝇有一个相对简单的神经系统，比在小鼠中发现的更复杂的神经系统更容易接近和更容易研究。苍蝇非常适合应用遗传学来研究其生物学。例如，果蝇生长迅速，因此可以进行基因筛选;即。打破基因，这是一个揭示事物如何运作的强有力的方法。在这个项目中，我们专注于神经系统的修剪。在这里，苍蝇提供了一个很好的机会，因为它的许多神经细胞在变态过程中回收，当蛆变成苍蝇。修剪对回收过程很重要。我们研究神经细胞如何通过使用水母的荧光“发光”基因进行修剪，这使我们能够看到活动物体内的神经细胞。利用这些发光的神经细胞和苍蝇遗传学，我们发现一种称为运输所需的内体分选复合物（ESCRT）的蛋白质家族对修剪很重要。这些ESCRT蛋白组装在一起，形成一个切割细胞膜的机器。因为细胞实际上是一个包含不同成分的膜的大系统，这组蛋白质是重要的，并用于细胞不同部分的许多不同过程，例如，当细胞一分为二时，它们也被使用。为了安排这些蛋白质完成每一项特定的任务，它们有非常特定的适配器，指导它们在正确的时间在正确的地方工作。我们认为，类似于细胞分裂时发生的切割的事情也发生在神经细胞分支修剪过程中。我们是第一个有证据表明ESCRT机制参与切割神经细胞分支的人。因为这一观察结果为我们提供了一个新的线索，关于神经系统中调节修剪的基因和机制，这是一个非常重要的观察结果。我们现在要确认这些意见并加以扩展。我们想知道哪些ESCRT家族成员对修剪很重要，哪些不重要;这些机器如何组装，在分支被切割的地方是否真的需要它们，以及切割过程如何由适配器控制。我们希望我们的工作将解决这个谜团的一部分，并且在未来，我们的工作可以帮助了解当人类神经系统疾病中的布线出错时会发生什么，并且，通过扩展可以开发什么治疗方法来纠正这些缺陷或减轻它们对心理健康和福祉的影响。

项目成果

Extensive and diverse patterns of cell death sculpt neural networks in insects.

细胞死亡的广泛而多样的模式雕刻昆虫中的神经网络。

• DOI: 10.7554/elife.59566
• 发表时间: 2020-09-07
• 期刊: eLife
• 影响因子: 7.7
• 作者: Pop S;Chen CL;Sproston CJ;Kondo S;Ramdya P;Williams DW
• 通讯作者: Williams DW

Neurexin and Neuroligin-based adhesion complexes drive axonal arborisation growth independent of synaptic activity

• DOI: 10.1101/182808
• 发表时间: 2017-08
• 期刊: eLife
• 影响因子: 7.7
• 作者: William D Constance;A. Mukherjee;Yvette E. Fisher;S. Pop;E. Blanc;Y. Toyama;Darren W. Williams

An ESCRT module is required for neuron pruning.

• DOI: 10.1038/srep08461
• 发表时间: 2015-02-13
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Loncle N;Agromayor M;Martin-Serrano J;Williams DW
• 通讯作者: Williams DW

Neurexin and Neuroligin-based adhesion complexes drive axonal arborisation growth independent of synaptic activity.

基于 Neurexin 和 Neuroligin 的粘附复合物可独立于突触活动驱动轴突树枝化生长。

• DOI: 10.7554/elife.31659
• 发表时间: 2018-03-05
• 期刊: eLife
• 影响因子: 7.7
• 作者: Constance WD;Mukherjee A;Fisher YE;Pop S;Blanc E;Toyama Y;Williams DW
• 通讯作者: Williams DW