Mechanisms for regulating mammalian axon guidance by differential sulphation of heparan sulphate.

我们的大脑是一个非常复杂的器官。为了有效地发挥作用，必须在相距很远的细胞之间建立精确的连接。眼睛视网膜上的细胞，称为视网膜神经节细胞，发出被称为轴突的精细过程，轴突沿着预定的路径（我们称之为“导航”的过程）移动，并连接到大脑内的专门细胞（它们的“目标”），这些细胞将把我们视网膜收集的视觉信息传递给处理成图像。那么，视网膜轴突是如何从眼睛到达大脑的目标而不误入歧途的呢？有点像我们用地图从一个地方导航到另一个地方，并决定在十字路口向左或向右转以到达目的地，视网膜轴突对来自环境的信号做出反应，告诉它们该走哪条路。这些信号是由大脑的不同区域产生的化学物质，它们吸引或排斥轴突，从而引导轴突沿着正确的路径前进。这些信号由轴突表面的受体识别，这些受体使轴突向一个方向或另一个方向转动。如果化学信号是错误的，或者轴突上对化学信号做出反应的受体异常，轴突就会做出错误的决定。这个过程如何出错的一个例子是特殊的糖或？糖蛋白sidechains吗?在细胞表面发现的结构不正确。这导致视网膜轴突对大脑告诉它们转向哪里的提示没有反应，最终到达了大脑的错误区域。我们还不知道为什么某些糖蛋白侧链的结构问题会引起轴突的问题？恰当地导航到目标的能力；本提案中的实验旨在找出答案。为了研究这个问题，我们将破坏特定糖蛋白侧链的形成，看看这是如何影响轴突在大脑中找到目标的能力的。确定当特定的糖结构没有正确形成时会发生什么，将使我们开始了解这些糖在视觉系统正常发育中的作用。在未来，我们可能能够利用我们对轴突从眼睛到大脑的引导的正常过程的知识来修复因疾病或损伤而丢失的视网膜轴突。

Our brain is an organ of fascinating complexity. To function effectively precise connections must be made between cells which are often far apart. Cells in the retina of the eye, called retinal ganglion cells, send out fine processes called axons, which travel along predefined pathways (a process we call ?navigation?) and connect to specialised cells (their ?targets?) within the brain which will transmit visual information collected by our retinas for processing into images. So how do retinal axons make the long journey from the eye to their targets in the brain without going astray? A little like us using a map to navigate from one location to another and deciding whether to turn left or right at a junction to reach our destination, retinal axons respond to signals from their environment to tell them which way to go. These signals are chemicals produced by the different areas of the brain which attract or repel axons and so guide them along the correct path. These signals are identified by receptors on the surface of the axon which cause the axon to turn one way or the other. Axons can make wrong decisions if either the chemical cues are wrong or if the receptors on the axons that respond to the chemical cues are abnormal. One example of how this process can go awry is where special sugars or ?glycoprotein sidechains? found on the surface of cells are not constructed properly. This results in retinal axons failing to respond to cues in the brain telling them where to turn, and ending up in the wrong areas of the brain. We do not yet know why problems with the structure of certain glycoprotein sidechains give rise to problems in the axon?s ability to navigate appropriately to their targets; the experiments in this proposal aim to find out. To investigate this question we will disrupt the formation of particular glycoprotein sidechains and see how this affects the ability of axons to find their targets in the brain. Identifying what happens when particular sugar structures are not formed correctly will allow us to begin to understand the role of these sugars during normal development of the visual system. In the future we may be able to use our knowledge of the normal processed involved in guidance of axons from the eye to the brain to repair retinal axons lost either by disease or injury.