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EphrinA reverse signalling in retinal axon guidance

EphrinA 视网膜轴突引导中的反向信号传导

基本信息

批准号：
BB/E015522/1
负责人：
Uwe Drescher
金额：
$ 52.63万
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：
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%2FE015522%2F1
关键词：
EphrinA reverse signalling retinal axon

项目摘要

During development of the nervous system, large numbers of cells called neurons are generated, which are connected to each other by long cables called axons. These axons are very important for the function of the brain. The axons are often quite long, and a main question in developmental neurobiology is how this axon wiring is achieved. In principle, it can be described such that there is a road map consisting of a number of different guide post molecules positioned at different places between two different neurons which tell these axons which way to go. A number of these molecules have been identified and we would like to understand how they tell the axons which way they have to go to find their other neuron. It might work like this: on the axons there are other molecules which bind the guide post molecules, such that, for example, for guide post molecules named 'ephrins' there are corresponding counter-molecules called 'Ephs' on the axons, which interact only with 'ephrins', and not for example with 'netrins', which is another class of guide post molecules. In fact, the molecules which we would like to understand are these Ephs and ephrins. The contact of an eph molecule on axons with ephrins positioned on the road results in avoidance of this area by this axon. Symbolically, in terms of the road map, it might mean that the car (cable) would approach a one-way street from the wrong side and would turn away. This behaviour is called 'repulsion'. There are other guide post molecules such as netrins, which induce the opposite reaction that is (in this picture) approaching the one-way street from the correct site, inducing an 'attraction', that is the car would drive into this road. For the repulsion, mediated by ephrins, we would like to understand what happens at the very tip of the axon/cable, which is called a growth cone, and when viewed by under a microscope, has a hand-like structure. Inside this growth cone there is a network of tubes and pipes, which are constantly destroyed and re-built, the local balance of which determines the direction in which the growth cone migrates. The Ephs and ephrins control the location and the rate by which the tubes and pipes are destroyed and rebuilt. However, at present the link between the Ephs and ephrins on the one hand, and the tubes inside the growth cone is not clear. In this approach we have designed some experiments to understand this link (in our terms signalling pathways) better. We will use axons from the retina, which normally grow into a part of the brain called the tectum. These retinal axons are very good characterised and some tests are available to analyse the function of Ephs and ephrins. From other guide post systems there are some types of links known, and we will investigate whether these links are also important for Ephs, ephrins and these retinal axons. A point we would like to investigate is the surprising finding that the guide post molecules, the ephrins, can also be expressed on the cables/axons and the Ephs can be found as guide post cells. The meaning of this reversed expression pattern will be a major part of this application.

在神经系统的发育过程中，产生了大量称为神经元的细胞，这些细胞通过称为轴突的长电缆相互连接。这些轴突对大脑的功能非常重要。轴突通常很长，发育神经生物学中的一个主要问题是如何实现轴突连接。原则上，它可以被描述为一个路线图，由位于两个不同神经元之间不同位置的许多不同的引导柱分子组成，它们告诉这些轴突走哪条路。其中一些分子已经被鉴定出来，我们想知道它们是如何告诉轴突它们必须走哪条路才能找到另一个神经元的。它可能是这样工作的：在轴突上，存在结合导向柱分子的其它分子，使得例如对于名为"ephrin"的导向柱分子，在轴突上存在相应的称为"Eph"的反分子，其仅与"ephrin"相互作用，而不与例如"netrins"相互作用，"netrins"是另一类导向柱分子。事实上，我们想要了解的分子是这些Ephs和ephrin。轴突上的ephh分子与位于道路上的ephrin的接触导致轴突避开该区域。从象征意义上说，就路线图而言，这可能意味着汽车（电缆）将从错误的一侧进入单行道，然后掉头离开。这种行为被称为“排斥”。还有其他的导向柱分子，如netrins，它诱导相反的反应，即（在这张照片中）从正确的位置接近单行道，诱导“吸引力”，即汽车会驶入这条路。对于由ephrins介导的排斥，我们想了解轴突/电缆的尖端发生了什么，这被称为生长锥，当在显微镜下观察时，具有手状结构。在这个生长锥内部，有一个不断被破坏和重建的管道网络，其局部平衡决定了生长锥迁移的方向。Ephs和ephrin控制三维布管的位置和销毁和重建速度。然而，目前，一方面，Ephs和ephrin之间的联系，以及生长锥内的管道还不清楚。在这种方法中，我们设计了一些实验来更好地理解这种联系（我们的术语信号通路）。我们将使用视网膜上的轴突，它们通常会生长成大脑的一部分，称为顶盖。这些视网膜轴突是非常好的特点和一些测试可用于分析的功能Ephs和ephrins。从其他的导柱系统有一些类型的链接已知的，我们将调查这些链接是否也是重要的Ephs，ephrins和这些视网膜轴突。我们想要研究的一点是令人惊讶的发现，即导向柱分子，ephrin，也可以在电缆/轴突上表达，并且可以发现Eph作为导向柱细胞。这种反向表达模式的含义将是本应用程序的主要部分。