Evolution of the vertebrate inner ear: a gene network approach

眼睛、鼻子和耳朵不断地提供来自环境的信号，使我们能够相互交流，通过调整我们的行为来对变化做出反应，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，而同一门低等非脊椎动物的感官结构要复杂得多，通常由散布在全身的细胞组成。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生活方式转变为更积极的生活方式，包括狩猎食物和躲避捕食者，从而探索新的栖息地。因此，了解感觉器官的进化是理解人类进化之谜的重要一环。令人惊讶的是，我们对推动复杂感觉器官形成的机制知之甚少，这一建议以耳朵为模型器官来解决这个问题。我们最近利用现代分子技术，建立了控制高等脊椎动物雏鸟耳朵早期发育的“连线图”。我们已经确定了推动干细胞向耳朵分化的一些关键驱动因素，确定了它们在分子层次中的作用，以及这些事件是如何由DNA中所谓的“调节区”控制的。有了这张脊椎动物耳朵形成的蓝图，我们现在可以问：基本脊椎动物七鳃鳗和最接近的脊椎动物近亲海鞘的祖先‘接线图’是什么，以及允许复杂感官出现的分子机制是什么？我们将确定我们在雏鸟身上鉴定出的哪些成分也存在于七鳃鳗耳朵和海鞘的“祖先耳朵”中。所有三个物种中存在的分子将是最古老的线路图的一部分，而七鳃鳗和小鸡中存在的那些分子将描述脊椎动物的谱系。我们已经确定了控制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招募到古老的耳朵连线图中，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类似的区域，评估它们在所有三个物种中的活动，并使用分子工具来表征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接近的近亲中最古老的分子网络，以及在进化过程中增加了耳朵形成连线图复杂性的分子事件。因此，该项目将对我们对脊椎动物进化的理解做出重要贡献，特别是突出那些允许出现复杂结构的事件，这些复杂结构定义了人类器官的功能，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.