Development and function of the zebrafish vestibular system across the life course

内耳是感知声音、重力和运动的感觉器官，使我们能够正确地听到和保持平衡。在耳内，感觉毛细胞检测重力以及身体在各个方向的运动。这种感觉信息通过大脑传递给肌肉反射，使生物体能够保持平衡。内耳也被正确地称为迷路。耳的前庭（平衡）部分由三个平滑弯曲的管半规管管和几个相互连接的感觉腔组成，这些感觉腔容纳了耳的感觉细胞。整个器官是一个连续的充满液体的腔。这种美丽而复杂的结构在所有脊椎动物中基本上都是相似的，从鱼类（我们在这里用作模型系统）到人类。内耳在胚胎中由一个简单的细胞球发育而成，而将这种基本结构转变为成熟耳朵的复杂迷路的细胞和组织重排确实是显着的。细胞片必须生长、弯曲、融合和重新排列。不同的细胞采取广泛不同的大小和形状来实现这一点。必须严格控制这些事件，以确保在正确的时间和地点产生正确的细胞类型和组织形状。我们在这项提案中的主要目的是使用尖端的成像技术来描述和理解这些细胞重排。我们使用斑马鱼作为我们的模型系统，因为它非常适合这种成像方法。斑马鱼胚胎在光学上是透明的，这意味着我们可以在显微镜下看到活体动物的内部器官，而不需要进行任何解剖。其次，我们可以用荧光蛋白标记细胞，随着它们的发展照亮不同的结构。通过使用专门的显微镜，我们可以测量整个器官在活胚胎中发育时细胞形状和组织运动的动态变化。我们将在鱼的整个生命过程中进行这些研究，包括胚胎发育，变态和成年期的事件。该项目的一个主要目标是与工程师建立新的联系，他们将使用我们的成像数据开发细胞如何改变形状，移动，融合和重新排列形成耳朵的精细结构。2我们也希望了解在胚胎发育过程中控制耳朵发育的遗传因素。在我们以前的工作中，我们已经确定了一些对半规管系统发育至关重要的基因。我们的一些鱼类品系在这些基因中携带特定的基因突变：我们将在上述成像和计算机建模实验中使用这些突变的鱼类，以获得关于基因功能如何影响内耳发育时细胞运动，细胞分裂和细胞形状的新见解。我们的几种遗传菌株在半规管系统中存在解剖缺陷，并且具有轻度平衡缺陷。我们将使用这些鱼来了解耳朵对平衡功能的贡献，使用自动跟踪游泳行为。这将使我们对耳朵的平衡系统的功能有新的认识，以及它与视觉和其他功能相比的相对重要性。与耳朵的听觉部分相比，对前庭（平衡）系统的研究远远不够，尽管前庭疾病很常见，并会导致严重的临床问题，特别是在老年人中。该项目将有助于纠正这种差异，并将有助于巩固我们对人类内耳健康和疾病的理解的知识基础。我们还旨在揭示基本的发育原则，这将提高我们对器官系统如何从发育胚胎中的细胞片中构建的理解。

The inner ear is the sensory organ that detects sound, gravity and motion, enabling us to hear and to balance correctly. Within the ear, sensory hair cells detect gravity together with body movement in all directions. This sensory information is relayed, via the brain, to muscular reflexes to enable an organism to maintain balance.The inner ear is rightly also called the labyrinth. The vestibular (balance) part of the ear consists of three smoothly curved tubes-the semicircular canal ducts-together with several interlinked sensory chambers, which house the sensory cells of the ear. The whole organ is one continuous fluid-filled cavity. This beautiful and intricate structure is essentially similar in all vertebrate organisms, from the fish (which we use here as a model system) through to humans. The inner ear develops in the embryo from a simple ball of cells, and the cell and tissue rearrangements that convert this rudimentary structure into the complex labyrinth of the mature ear are truly remarkable. Sheets of cells must grow, bend, fuse and rearrange. Different cells take on widely differing sizes and shapes to achieve this. These events must be tightly controlled to ensure that the correct cell types and tissue shapes are produced in the right place and at the right time. Our primary aim in this proposal is to use cutting-edge imaging technology to describe and understand these cellular rearrangements. We use the zebrafish as our model system, as it is beautifully suited to this imaging approach. The zebrafish embryo is optically clear, meaning that we can see internal organs in the live animal under the microscope, without any need for dissection. Secondly, we can label cells with fluorescent proteins, lighting up different structures as they develop. By using specialised microscopes, we can measure dynamic changes in cell shapes and tissue movements as the whole organ develops in the live embryo. We will undertake these studies across the life course of the fish, including events during embryogenesis, metamorphosis and adulthood.A major goal of the project is to develop and forge new links with engineers, who will use our imaging data to develop computer models of how cells change shape, move, fuse and rearrange to form the elaborate structures of the ear.We also wish to understand the genetic factors that control ear development during embryogenesis. In our previous work, we have identified a number of genes that are critical for development of the semicircular canal system. A number of our fish strains carry specific genetic mutations in these genes: we will use these mutant fish in the imaging and computer modelling experiments described above, to gain new insights into how gene function affects cell movement, cell division and cell shape as the inner ear develops.A final aim is to correlate our imaging data with vestibular behaviour in our fish. Several of our genetic strains develop with anatomical defects in the semicircular canal system, and have mild balance defects. We will use these fish to understand the contribution of the ear to balance function, using automated tracking of swimming behaviour. This will give us new insights into the function of the balance system of the ear, and its relative importance compared with visual and other functions.Research on the vestibular (balance) system is hugely under-represented compared with that on the auditory (hearing) part of the ear, despite the fact that vestibular disorders are common and cause significant clinical problems, especially in the elderly. This project will help to redress that discrepancy and will contribute to the knowledge base that underpins our understanding of the human inner ear in both health and disease. We also aim to uncover fundamental developmental principles that will improve our understanding of how organ systems are built from sheets of cells in the developing embryo.