Investigating the gene regulatory network underlying the segmentation clock of the flour beetle Tribolium castaneum

这项研究将确定节肢动物（如果蝇、甲虫和蜘蛛）和脊椎动物（如鱼、老鼠和人类）在胚胎发育过程中身体发育方式的重要异同。这项工作对于理解形成动物身体结构的遗传和发育机制如何在进化过程中发生变化和分化，从而产生我们今天在自然界中看到的不同类型的动物身体结构至关重要。这对于理解5.5亿年前进化史上所有动物的共同祖先是如何发展其身体结构的也很重要。人类和其他脊椎动物拥有分段的身体结构：我们身体的内部部分被分成分离和重复的结构，例如我们的椎骨和肋骨。脊椎动物胚胎在发育过程中，头结构首先形成，躯干按前向后的顺序生长。在这一过程中，将会发育成肋骨/椎骨的细胞群是按照前到后的顺序，一个接一个地提前确定的。这个过程是由一个基因网络控制的，这个基因网络被反复打开和关闭，以定义每一组细胞（即每一根未来的肋骨/脊椎）。这种复杂的基因振荡网络被称为脊椎动物分割时钟。节肢动物，包括果蝇、甲虫和蜘蛛，也有明显的分段身体。赤粉甲虫（Tribolium castaneum）的腹部部分在甲虫发育过程中依次形成，一个接一个，其过程类似于上述脊椎动物的过程。我最近的研究表明，这一发育过程也是由一个基因网络控制的，该基因网络以顺序模式振荡腹部节段-节肢动物节段时钟。有趣的是，果蝇黑腹果蝇已经进化到加速其发育，以至于所有身体部分在卵子中同时形成，生物学家已经在遗传水平上很好地理解了这一过程。这项工作计划的第一个目标是确定节肢动物分割时钟的基因网络是否以类似的方式组织与脊椎动物分割时钟。如果发现惊人的相似性，这可能表明分割时钟是节肢动物和脊椎动物共同祖先的一个特征。或者，如果存在显著差异，则可能表明不同的动物群体独立平行地进化出了相似的遗传机制。不管怎样，这项研究有望揭示人类进化史的重要信息。本工作计划的第二个目标是确定涉及片段时钟的顺序片段机制如何在进化中被修改以产生控制果蝇片段同时形成的机制。确定促进这种转变的基因调控的变化，可以揭示发育机制进化产生我们今天在自然界中看到的各种动物身体结构的一般原理。这项工作计划的第三个目标是开发新的遗传技术，将推动三角虫作为一种廉价、可适应、道德上可接受的无脊椎动物模型来研究分割时钟。公众将从这项研究中受益，通过增加我们对人类和动物进化的理解，通过开发一个强大的无脊椎动物遗传模型来研究分割时钟的遗传原理，从而减少目前对道德上不太可接受的脊椎动物模型的依赖，以及通过使用Tribolium从未来的分割时钟研究中获得更好的价值。这是一种比脊椎动物模型更便宜、更容易适应的替代品。

This research will identify important similarities and differences in the way animals as diverse as arthropods (i.e. fruit flies, beetles and spiders) and vertebrates (i.e. fish, mice and humans) develop their body during embryogenesis. This work is crucial for understanding how the genetic and developmental mechanisms forming animal body plans changed and diverged over evolutionary time to produce the diverse types of animal body plans we see in nature today. It is also important for understanding how the common ancestor of all animals developed its body plan, deep in evolutionary history, over 550 million years ago. Humans, and other vertebrates, possess a segmented body plan: internal parts of our body are divided into separated and repeated structures, for example our vertebrae and ribs. Vertebrate embryos grow during their development, with head structures formed first and the trunk grown in an anterior to posterior sequence. During this process, the cell populations that will later give rise to ribs/vertebrae are determined early, and one-by-one, in an anterior to posterior sequence. This process is controlled by a network of genes that are repeatedly turned on and off to define each group of cells (i.e. each future rib/vertebra). This complex oscillating network of genes is called the vertebrate segmentation clock. Arthropods, including fruit flies, beetles and spiders, also have a visibly segmented body plan. The abdominal body segments of the red flour beetle Tribolium castaneum form sequentially, one-by-one, in an anterior to posterior progression during beetle development, in a process similar to that described above for vertebrates. I have recently shown that this developmental process is also controlled by a network of genes that oscillate to sequentially pattern abdominal segments - the arthropod segmentation clock. Interestingly, the fruit fly Drosophila melanogaster has evolved to speed up its development, such that all body segments form simultaneously in the egg in a process that is already well understood at the genetic level by biologists.The first objective of this work programme is to determine whether the gene network underlying the arthropod segmentation clock is organized in a similar way to the vertebrate segmentation clock. If striking similarities are found, it could suggest that the segmentation clock was a feature of the common ancestor of arthropods and vertebrates. Alternatively, if there are striking differences, it could suggest that disparate animal groups have evolved similar genetic mechanisms independently and in parallel. Either way, this research promises to reveal important information about our evolutionary history.The second objective of this work programme is to determine how a sequential segmentation mechanism involving a segmentation clock was modified in evolution to produce the mechanism controlling the simultaneous formation of segments in Drosophila. Identifying the changes in gene regulation that facilitated this transition could reveal general principles by which developmental mechanisms evolved to produce the wide variety of animal body plans we see in nature today.The third objective of this work programme is to develop new genetic techniques that will advance Tribolium castaneum as a cheap, amenable, ethically acceptable, invertebrate model with which to study segmentation clocks. The general public will benefit from this research via an increase in our understanding of human and animal evolution, through the development of a powerful invertebrate genetic model for studying the genetic principles underlying segmentation clocks thus reducing the current dependence on less ethically acceptable vertebrate models, and through better value for money from future research on segmentation clocks via the use of Tribolium, a cheaper and potentially more amenable alternative to vertebrate models.