Uncovering the role of the ESCRT machinery in neuron pruning

就像电脑或任何其他复杂的电子设备一样，我们的大脑需要准确地连接在一起，才能正常工作。目前的想法表明，连接中断可能是许多精神障碍的基础，因此了解神经系统连接是如何出错的对于帮助治疗此类疾病非常重要。因此，这项工作很可能为医疗保健部门做出贡献，从而为我们的社会做出贡献。随着神经系统的形成，神经细胞不断生长，相互连接，就像电子设备的电线一样。当神经细胞生长时，它们以旺盛的方式生长，通常会产生许多延伸分支。其中一些分支机构进入了错误的领域，或者是多余的，需要移除。我们把这种砍掉树枝的行为称为‘修剪’。修剪多余或多余的分支对于调整神经系统以使其能够精确工作非常重要。在许多情况下，修剪是通过砍掉树枝来进行的，因此有了修剪这个术语。虽然我们对神经系统是如何发展的知道很多，但我们对树枝是如何在身体上被砍掉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分享了大部分基因，所以我们从苍蝇身上学到的东西可以很容易地转化为人类。同时，果蝇有一个相对简单的神经系统，比老鼠发现的更复杂的神经系统更容易接触和研究。苍蝇非常适合应用遗传学来研究它们的生物学。例如，果蝇生长得很快，所以人们可以进行基因筛查；即。破坏基因，这是揭示事物工作原理的一种强有力的方法。在这个项目中，我们关注的是神经系统的修剪。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蜕变过程中被循环利用，也就是蚯蚓变成苍蝇的时候。修剪对回收过程很重要。我们利用来自水母的荧光“发光”基因研究神经细胞是如何进行修剪的，这使我们能够看到活着的动物体内的神经细胞。利用这些发光的神经细胞和果蝇遗传学，我们发现一种名为运输所需的内体分类复合体(ESCRT)的蛋白质家族对修剪很重要。这些ESCRT蛋白组装在一起，形成一台切割细胞膜的机器。因为细胞实际上是一个包含不同成分的膜的大系统，所以这组蛋白质很重要，用于细胞不同部分的许多不同过程，例如当细胞分裂成两半时也使用它们。为了为每项特定的任务安排这些蛋白质，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点工作。我们认为，在神经细胞分支修剪过程中，细胞分裂时发生的切割也会发生。我们是第一批有证据表明ESCRT机制参与切断神经细胞分支的人。因为这项观察为我们提供了关于神经系统中调控修剪的基因和机制的新线索，这是一项非常重要的观察。我们现在要确认这些观察结果，并将其扩大。我们想知道哪些ESCRT家族成员对修剪是重要的，哪些不重要；这些机器是如何组装的，它们是否真的需要直接在枝条被切断的地方使用，以及适配器是如何控制切割过程的。我们希望我们的工作将解开这一谜团的一部分，并希望在未来我们的工作可以帮助理解当人类神经系统疾病的连接出现问题时会发生什么，以及由此可以开发出什么治疗方法来纠正这些缺陷或减少它们对心理健康和福祉的影响。

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.