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Axial patterning in the vertebrate inner ear: the role of Hedgehog signalling

脊椎动物内耳的轴向模式：刺猬信号传导的作用

基本信息

批准号：
BB/E015875/1
负责人：
Tanya Whitfield
金额：
$ 37.63万
依托单位：
University of Sheffield
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%2FE015875%2F1
关键词：
Axial patterning vertebrate inner ear

项目摘要

The inner ear is enormously important for the senses of balance and hearing. It consists of an intricate fluid-filled labyrinth housing a variety of extraordinarily sensitive sensory structures that respond to sound, movement and gravity. For correct inner ear function it is essential that each of these components form in exactly the right place, as any disturbance can lead to deafness or balance disorders. Indeed, congenital deafness is an important clinical problem, affecting approximately one in every thousand children at birth. Our aim is to understand how the inner ear develops in the embryo, and the mechanisms that ensure that the different cell types in the ear arise in the correct positions so that they can function accurately. We use embryos of a small tropical fish, the zebrafish, in our research, as it is a superb model for the study of vertebrate inner ear development. Importantly, zebrafish possess an inner ear that is very similar in most respects to those of other vertebrates like ourselves, and the embryo is transparent, meaning that the inner ear - even though an internal organ - can be visualised in the live organism. Moreover, the zebrafish is a powerful genetic organism, meaning that we can disrupt individual genes specifically to discover their function. Many different lines of zebrafish exist in which the ear develops with specific defects, or in which different cell types are marked with fluorescent dyes, and these can be used to identify key genes that are required for correct formation of the ear. In addition, embryos are abundant, easily available and amenable to manipulation. In this project, we will focus on understanding the effects of Hedgehog (Hh) proteins on ear development. Hh proteins are signalling molecules that give instructions to cells in the embryo, telling them how and where to develop. It is known that Hh has a crucial and early role in distinguishing one region of the ear from another, but its exact function is not fully understood. In particular, it does not seem to play the same role in zebrafish and mammals: in fish, it primarily regulates development of the anterior-posterior (head to tail) axis in the ear, whereas in mammals, its primary role is in regulation of the dorsal-ventral (back to belly) axis, which is perpendicular to the anterior-posterior axis. This is surprising, as the orientation of the inner ear in the head of the adult animal, and the majority of inner ear structures, are very similar between the two groups. Are mechanisms of ear development really so different in mammals and fish? It is important to answer this question, as the zebrafish is widely used as a model for human hearing and deafness. Our preliminary investigations now suggest that the role of Hh is more similar between mouse and zebrafish than it first appears. In particular, our studies indicate that Hh signalling is also involved in distinguishing between dorsal and ventral regions of the zebrafish inner ear. We aim to confirm this using a novel and unique panel of zebrafish mutants. In these fish, the function of genes that code for inhibitors of Hh signalling is disrupted, meaning that all cells now experience high levels of this signalling molecule. We will use these mutants to explore the mechanisms involved in formation of dorsal-ventral patterning in the zebrafish ear. In particular, we aim to establish exactly when Hh is acting during ear development, and whether it acts together with a second group of signalling molecules, those of the Wnt family, in patterning the ear. We will also test whether Hh has additional AP patterning roles in the developing inner ear of the mouse embryo. This work will lead to a greater understanding of how the inner ear develops in the vertebrate embryo, providing important basic knowledge that will help to inform clinical research into the many genetic conditions that lead to deafness in humans.

内耳对平衡和听觉非常重要。它由一个错综复杂的充满液体的迷宫组成，里面有各种对声音、运动和重力做出反应的异常敏感的感官结构。对于正确的内耳功能，至关重要的是，每一个组成部分都在正确的位置形成，因为任何干扰都可能导致耳聋或平衡障碍。事实上，先天性耳聋是一个重要的临床问题，大约每一千名出生的儿童中就有一名受到影响。我们的目标是了解内耳在胚胎中是如何发育的，以及确保耳朵中不同类型的细胞在正确的位置出现以使它们能够准确地发挥作用的机制。我们在研究中使用了一种小型热带鱼斑马鱼的胚胎，因为它是研究脊椎动物内耳发育的绝佳模型。重要的是，斑马鱼的内耳在大多数方面与其他脊椎动物（如人类）非常相似，而且胚胎是透明的，这意味着即使内耳是一个内部器官，也可以在活体中看到。此外，斑马鱼是一种强大的遗传生物，这意味着我们可以专门破坏单个基因来发现它们的功能。存在着许多不同种类的斑马鱼，它们的耳朵发育有特定的缺陷，或者它们的不同细胞类型被荧光染料标记，这些可以用来识别正确形成耳朵所需的关键基因。此外，胚胎数量丰富，容易获得，易于操作。在这个项目中，我们将重点了解Hedgehog （Hh）蛋白对耳朵发育的影响。Hh蛋白是一种信号分子，它向胚胎中的细胞发出指令，告诉它们如何以及在哪里发育。众所周知，Hh在区分耳朵的一个区域和另一个区域方面起着至关重要的作用，但其确切的功能尚不完全清楚。特别是，它在斑马鱼和哺乳动物中似乎没有发挥同样的作用：在鱼类中，它主要调节耳朵中前后轴（头到尾）的发育，而在哺乳动物中，它主要调节与前后轴垂直的背-腹轴（背到腹部）的发育。这是令人惊讶的，因为成年动物头部内耳的方向，以及大多数内耳结构，在两组之间非常相似。哺乳动物和鱼类的耳朵发育机制真的如此不同吗？回答这个问题很重要，因为斑马鱼被广泛用作人类听力和耳聋的模型。我们的初步研究现在表明Hh在小鼠和斑马鱼之间的作用比最初看起来更相似。特别是，我们的研究表明Hh信号也参与斑马鱼内耳背侧和腹侧区域的区分。我们的目标是用一种新颖独特的斑马鱼突变体来证实这一点。在这些鱼类中，编码Hh信号抑制剂的基因功能被破坏，这意味着所有细胞现在都经历了高水平的这种信号分子。我们将使用这些突变体来探索斑马鱼耳朵中背-腹模式形成的机制。特别是，我们的目标是确定Hh在耳朵发育过程中的确切作用时间，以及它是否与第二组信号分子（Wnt家族的分子）一起作用，以形成耳朵的模式。我们还将测试Hh是否在小鼠胚胎发育的内耳中具有额外的AP模式作用。这项工作将有助于更好地了解脊椎动物胚胎中内耳的发育方式，提供重要的基础知识，有助于为临床研究提供信息，了解导致人类耳聋的许多遗传条件。