Evolution of the vertebrate inner ear: a gene network approach

眼睛，鼻子和耳朵不断提供来自环境的信号，使我们能够相互沟通，通过调整我们的行为对变化做出反应，并在日常生活中导航世界。在包括人类在内的所有脊椎动物中，这些感觉器官非常复杂，集中在头部，而同一门的低级非脊椎动物的感觉结构则不那么复杂，通常由分散在全身的细胞组成。因此，人们认为脊椎动物进化的一个关键特征是感觉器官的出现：它们允许动物从被动的生活方式转变为更主动的生活方式，包括狩猎食物和逃避捕食者，从而探索新的栖息地。因此，理解感觉器官的进化是理解人类进化之谜的重要组成部分。令人惊讶的是，我们对驱动复杂感觉器官形成的机制知之甚少，而这一提议使用耳朵作为模型器官来解决这个问题。最近，我们利用现代分子技术建立了控制高等脊椎动物小鸡早期耳朵发育的“接线图”。我们已经确定了一些将干细胞推向耳朵身份的关键驱动因素，确定了它们如何在分子层次中发挥作用，以及这些事件如何由DNA中所谓的“调控区”控制。有了脊椎动物耳朵形成的蓝图，我们现在可以问：七鳃鳗这种基本脊椎动物和脊椎动物的近亲海鞘的祖先“接线图”是什么？是什么分子机制使得复杂的感觉器官得以出现？我们将确定哪些我们在小鸡身上发现的成分也存在于七鳃鳗的耳朵和海鞘的“祖先耳朵”中。存在于所有这三个物种的分子将是最古老的布线图的一部分，而那些存在于七鳃鳗和小鸡将是脊椎动物的谱系。我们已经确定了控制小鸡耳朵基因表达的调控区域。我们的假设是，这些调控元件的变化允许新基因进入古老的耳朵接线图，从而允许复杂的脊椎动物耳朵的进化。为了验证这一假设，我们将使用生物信息学和分子方法来识别七鳃鳗和海鞘中的相似区域，评估它们在所有三个物种中的活性，并使用分子工具来识别这些元素中最关键的部分。跨物种的比较将使我们能够定义脊椎动物最近亲属中最古老的分子网络，以及在进化过程中增加耳朵形成接线图复杂性的分子事件。因此，该项目将为我们理解脊椎动物进化做出重要贡献，特别是突出了允许定义人类器官功能的复杂结构出现的事件，这些结构是定义人类行为的关键。

The eye, nose and ear constantly provide signals from the environment that allow us to communicate with each other, to react to changes by adjusting our behaviour and to navigate the world throughout daily life. In all vertebrates, including humans, these sense organs are very complex and are concentrated in the head, while sensory structures in lower, non-vertebrate animals of the same phylum are much less sophisticated and generally consist of cells scattered across the body. It is therefore thought that a key feature that made the evolution of vertebrates possible is the emergence of sense organs: they allowed animals to move from a passive to a more active life style including hunting for food and escaping predators, and therefore to explore new habitats. Thus, understanding the evolution of sense organs is an important piece in the puzzle of understanding human evolution.Surprisingly, we know very little about the mechanisms that drove the formation of sophisticated sense organs, and this proposal addresses this question using the ear as a model organ. We have recently established the 'wiring diagram' that controls early ear development in a higher vertebrate, the chick, using modern molecular techniques. We have identified some of the key drivers that push stem cells towards ear identity, established how they act in a molecular hierarchy, and how these events are controlled by so called 'regulatory regions' in the DNA. With this blueprint for vertebrate ear formation, we can now ask: what was the ancestral 'wiring diagram' in a basic vertebrate, the lamprey, and the closest vertebrate relative, the sea squirt, and what are the molecular mechanisms that allowed the emergence of sophisticated sense organs? We will establish which of the components that we have identified in the chick are also present in the lamprey ear and in the 'ancestral ear' of the sea squirt. Molecules present in all three species will be part of the most ancient wiring diagram, while those present in lamprey and chick will characterise the vertebrate lineage.We have already characterised the regulatory regions that control the expression of ear genes in chick. Our hypothesis is that changes in these regulatory elements allowed the recruitment of new genes into the ancient ear wiring diagram and thus allowed evolution of sophisticated vertebrate ears. To test this hypothesis we will use bioinformatics and molecular approaches to identify similar regions in lamprey and the sea squirt, assess their activity across all three species and use molecular tools to characterise the most crucial parts of these elements. Comparison across species will allow us to define the most ancient molecular network in the closest relative of vertebrates, as well as the molecular events that increased complexity of the wiring diagram for ear formation during evolution. This project will therefore make an important contribution to our understanding of vertebrate evolution, in particular highlighting the events that allowed the emergences of sophisticated structures that define the function of human organs and are key to define human behaviour.