Molecular reconstitution of cellular machinery essential for neuronal development

当你还是个孩子的时候，你有没有在超市高耸的货架中迷路过？这种在巨大而复杂的环境中感觉到非常小的东西让人想起发育中的大脑细胞所面临的挑战。成年人的大脑由数十亿个称为神经元的特殊细胞组成。在胚胎生长期间，未成熟的神经元进行了一次惊人的旅程，包括从发育中的大脑中心找到它们的方式，推动许多其他神经元到达大脑复杂结构中的特定位置。成功的迁移使成熟神经元网络的形成成为可能，这些神经元网络对记忆和思维至关重要。如果神经元在它们的旅程中丢失，可能会导致严重的人类疾病，包括癫痫和智力迟钝，以及过早死亡。我实验室的工作开始提供对机制组件的理解，这些机制使神经元能够在发育中的大脑的复杂迷宫中导航。就像我们的身体有一个骨架一样，神经元也有一个骨架-称为细胞骨架-它也提供支持和力量。细胞骨架参与细胞生命的许多重要方面，包括细胞的形状和运动，它对大脑发育至关重要。研究细胞骨架很重要，这样我们就可以了解健康细胞如何工作以及疾病中细胞骨架的功能障碍。我的研究团队研究细胞骨架的三维结构，因为了解细胞骨架的样子有助于我们了解它在细胞内是如何工作的。我们用高倍显微镜拍摄单个细胞骨架分子的照片，然后用计算机将这些照片联合收割机组合起来，计算出它们的三维形状。我们目前的研究集中在细胞骨架的一部分，称为微管，长圆柱形结构，作为支架，以帮助神经元的运动。在这个项目中，我们将研究一个为神经元中的微管提供额外稳定性的蛋白质家族。这些蛋白质被称为微管相关蛋白的doublecortin家族，它们对人类大脑发育至关重要。我们最近从显微镜研究中获得了一些令人兴奋的结果，我们想更多地了解这些蛋白质如何与微管相互作用，为迁移的神经元提供力量。我们还想知道双皮质素家族对微管的稳定作用是如何影响神经元的转运马达的，这些马达使用微管作为轨道在细胞内运送货物。有了这些信息，我们希望能够深入了解大脑发育疾病是如何发生的。我们的研究还应该提供有关如何使用未成熟脑细胞治疗晚年脑损伤的重要线索，例如中风患者或阿尔茨海默病等神经退行性疾病患者。

When you were a child, did you ever get lost amidst the towering shelves of a supermarket? That sense of something very small in a huge and complex environment is reminiscent of the challenge faced by cells of the developing brain. The adult human brain is built from billions of specialised cells called neurons. During embryonic growth, immature neurons undertake an amazing journey that involves finding their way from the centre of the developing brain, pushing past many other neurons to get to specific locations in the brain's complex structure. Successful migration enables the formation of the network of mature neurons that are essential for memory and thought. Severe human diseases including epilepsy and mental retardation, and early death, can be caused if the neurons get lost on their journey. Work in my lab is beginning to provide understanding about components of the machinery that enable neurons to navigate the complex maze of the developing brain. In the same way as our body has a skeleton, neurons have a skeleton - called the cytoskeleton - which also provides support and strength. The cytoskeleton is involved in many important aspects of the life of the cell, including cell shape and movement and it is essential for brain development. Studying the cytoskeleton is important so we can understand both how healthy cells work and malfunctions of the cytoskeleton in disease. My research team studies the three-dimensional structure of the cytoskeleton, because knowing what the cytoskeleton looks like contributes to our understanding of how it works within the cell. We use a very powerful microscope to take pictures of individual cytoskeleton molecules and then use computers to combine these pictures and calculate their three-dimensional shape. Our current research focuses on a part of the cytoskeleton called microtubules, long cylindrical structures that act as scaffolds to help neurons on the move. In this project, we will be studying a family of proteins that provide extra stability for microtubules in neurons. These proteins are called the doublecortin family of microtubule associated proteins, and they are essential for human brain development. We have had some exciting recent results from our microscope studies and we want to know more about how these proteins interact with microtubules to provide strength for migrating neurons. We also want to know how microtubule stabilisation by the doublecortin family affects the neuron's transporter motors that use microtubules as tracks to carry cargo around the cell. With this information, we hope to provide insight into how diseases of brain development occur. Our research should also provide essential clues about how immature brain cells might be used to treat brain damage later in life, for example in stroke patients or in sufferers of neurodegenerative diseases like Alzheimer's disease.