Interpretation of guidance cues by the actin-binding protein Drebrin to direct collective neuronal migration

形成一个拥有数十亿神经细胞和数万亿连接的人脑是一个极其复杂的过程，几乎没有错误的余地。在胚胎和儿童早期的大脑发育过程中，许多神经细胞必须从它们出生的位置迁移到回路中正确的最终位置。为了做到这一点，它们利用表面的蛋白质对周围组织的信号做出反应。这些线索随后被细胞内的其他蛋白质翻译，从而移动并引导它们到适当的位置。如果这个环节出了问题，那么神经细胞就无法建立正确的连接，大脑就无法运作：它无法形成记忆，无法处理感觉输入，也无法产生运动输出。从复杂的认知行为到对身体的基本控制，大脑功能的各个方面都可能受到损害。神经细胞之间的连接在人的一生中不断地更新和替换。人们普遍认为，形成新联系或加强现有联系的能力是物体识别和记忆形成的基础。然而，随着我们年龄的增长，这些连接变得不那么活跃，它们往往更容易崩溃，修复效率也更低，从而导致与衰老相关的记忆丧失和痴呆。其中一个原因被认为是，在生命早期驱动大脑形成的蛋白质在成年后变得不那么丰富，因此其维持和修复自身的能力越来越受到损害。因此，了解负责连接大脑的蛋白质可能会揭示生命周期的另一端，并揭示重新激活修复过程的方法。我们的研究集中在这样一种蛋白质上，它可能在塑造大脑并使其在一生中保持功能方面发挥重要作用。这种被称为Drebrin的蛋白质在发育过程中对某些神经细胞的迁移能力至关重要，然后维持它们之间的联系，但它是如何做到这一点的尚不清楚。显然，我们需要更多地了解这种蛋白质，以及它在协调大脑形成中的作用，以及它如何以及为什么会随着年龄的增长而退化。我们将使用基因工具来改变神经细胞产生的德雷布林的数量，并分析这对大脑发育过程中它们的形状和运动的影响。Drebrin及其相互作用的蛋白质将被贴上不同颜色的荧光标签，并被引入组织培养皿中正在生长的神经细胞中。这些标签就像分子灯泡一样，可以用激光照射的特殊显微镜对其进行数字拍摄。由此产生的视频将使我们能够可视化标记蛋白质在活细胞内的相对运动，并观察它们在正常细胞中的行为。然后将这些与Drebrin和/或其伴生蛋白被移除或突变的细胞影像进行比较，以便量化对神经细胞形状和运动的影响。然后，我们将从小鸡胚胎大脑的神经细胞中移除这些蛋白质，看看它们是如何影响大脑发育的。这项研究至关重要，因为它将为神经细胞如何在发育中的神经系统中找到自己的方式提供新颖而令人兴奋的信息。我们将分析它们是单独完成这项壮举，还是成群结队地跟随一组先锋细胞。我们将研究细胞如何设法将无数的外部线索转化为它们形状和运动的正确变化。更好地了解发育过程中涉及的关键蛋白质，将极大地提高我们将其应用于理解大脑衰老以及它如何以及为什么失去功能的能力。人们的寿命越来越长；作为一个整体，人口正在老龄化，因此，为了提高生活质量，解决这种人口结构变化对社会和经济的影响，这项研究既是必要的，也是及时的。

Forming a human brain with its billions of nerve cells and trillions of connections is a fantastically complex process with little margin for error. During brain growth in the embryo and early childhood, many nerve cells have to migrate from their site of birth to their correct final location within the circuitry. To do this they use proteins on their surface to respond to signals in the tissue around them. These cues are then translated by other proteins inside the cells to move and steer them to the appropriate place. If this goes wrong, then nerve cells do not make the right connections and the brain cannot function: it cannot form memories, process sensory inputs or produce motor outputs. Every aspect of brain function from sophisticated cognitive behaviour to basic control of the body can be compromised. The connections between nerve cells are continually renewed and replaced throughout life. The ability to form new links or reinforce existing ones is widely believed to underlie object recognition and memory formation. However, as we grow older the connections become less dynamic, they tend to break down more often and be repaired less efficiently, resulting in the memory loss and dementia associated with ageing. One of the reasons for this is thought to be that the proteins driving brain formation early in life become less abundant in the adult hence its ability to maintain and repair itself becomes increasingly compromised. Therefore, understanding the proteins that are responsible for wiring up the brain is likely to shed light on the other end of the life cycle and reveal ways to reactivate the repair processes. Our research focusses on such a protein that could play an important role shaping brains and then keeping them functioning throughout life. This protein, called Drebrin, is essential for the migratory ability of certain nerve cells during development and then maintaining the contacts between them but how it does so remains unknown. There is a clear need to understand more about this protein and the role it plays in co-ordinating brain formation and how and why it deteriorates with age. We will use genetic tools to change the amount of Drebrin produced by nerve cells and analyse the effect this has on their shape and movement during brain development. Drebrin and the proteins with which it interacts will be labelled with different coloured fluorescent tags and introduced into growing nerve cells in tissue culture dishes. The tags will act like molecular light bulbs that can be digitally filmed using a special microscope illuminated by lasers. The resultant movies will enable us to visualise the relative motions of the tagged proteins inside living cells and watch their behaviour in normal cells. These will then be compared to movies of cells in which Drebrin and/or its partner proteins have been removed or mutated so that the effects on nerve cell shape and movement can be quantified. We will then genetically remove these proteins from nerve cells in embryonic chick brains to see how they influence actual brain development. This research is of vital importance because it will provide novel and exciting information about how nerve cells find their way around the developing nervous system. We will analyse whether they perform this feat individually or if they navigate as a collective mass following a set of pioneer cells. We will investigate how the cells manage to translate a myriad of external cues into the correct changes in their shape and movement. Better knowledge of the key proteins involved in development will greatly enhance our ability to apply this to understanding the ageing brain and how and why it loses its function. People are living longer; the population as a whole is ageing so this research is both necessary and timely in order to improve quality of life and tackle the social and economic impacts of this demographic shift.