Robust scaling and self-organisation of the Drosophila anteroposterior axis

果蝇前后轴的稳健缩放和自组织

• 批准号: BB/Y00020X/1
• 负责人: Steven Russell
• 金额: $ 83万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY00020X%2F1
• 关键词: Robust; scaling; self; organisation; Drosophila

BACKGROUNDAn adult organism contains many different types of cells, organised into a complicated but orderly arrangement. Embryo patterning is the field of developmental biology concerned with how this complicated arrangement is created.Embryo patterning is typically robust, producing reliable outputs despite variable inputs and conditions. It can scale (adapt proportionally to embryo size), for example during the production of twins. Finally, it requires a great deal of self-organisation (emergence of high level pattern from lower level processes), since the adult organism is much more complicated than the initial fertilised egg.Embryo patterning has been studied for decades, using a mixture of "model organism" experiments and mathematical theory. However, prevailing theories struggle to account for the robustness, scalability and self-organisation observed during experimental manipulations, indicating a serious mismatch with biological reality.This mismatch is particularly apparent in the early Drosophila (fruit fly) embryo, an important model system that is simpler, more extensively studied, and more conducive to genetic experiments than most other species. The early stages of Drosophila's anteroposterior (head-to-tail) patterning are more robust than we can account for, even though we know the 15 genes involved, the 4 initial signals laid down by the embryo's mother that they respond to, and some of the regulatory interactions between these components.HYPOTHESISWe believe that the robustness of Drosophila patterning emerges from the structure of the whole early anteroposterior patterning network (the full set of regulatory interactions between the 15 genes and their 4 inputs), combined with the fact that the mRNA and protein molecules expressed from these genes diffuse between nearby nuclei. While there are thousands of nuclei in the early Drosophila embryo, cell membranes do not form between them until after the initial anteroposterior pattern is laid down. We hypothesise that the patterning network exploits the spatial interactions between nuclei to generate pattern regulation at the level of the whole tissue; this idea contrasts with the mathematical models currently applied to the Drosophila embryo, which assume that the inputs to patterning will be interpreted (read-out) locally.OBJECTIVESWe aim to resolve the structure of the patterning network, and explain why it so reliably produces an output close to the wild-type (normal) embryo pattern, even if the starting conditions in the embryo are quite strongly perturbed. We will then use this new understanding of patterning in the Drosophila embryo to extract new general principles that can be used to understand developmental patterning in other animal embryos, or in the synthetic embryo-like structures that can now be generated from stem cells.APPROACHThis is an interdisciplinary proposal, which combines microscopy, genetics, and mathematical modelling. We will use cutting-edge imaging approaches to reveal how patterning unfolds within wild-type and mutant embryos, then use computational simulations to understand how these behaviours are produced by the underlying gene network.POTENTIAL APPLICATIONS AND BENEFITSThis work will advance our basic understanding of embryonic development, by solving a long-standing and fundamental problem. Our findings will be directly relevant to developmental biologists (both Drosophila researchers and those studying other animal systems), plus mathematical biologists studying patterning from a theoretical perspective. The principles we uncover will also have practical applications in synthetic and stem cell biology, contributing to long-term translational applications in developmental disease, regeneration, and bioengineering.

后台成人有机体包含许多不同类型的细胞，分为复杂但有序的排列。胚胎模式是发展生物学领域，涉及如何创建这种复杂的布置。Embryo构图通常是稳健的，尽管输入和条件可变，但仍会产生可靠的输出。它可以扩展（按比例适应胚胎大小），例如在生产双胞胎期间。最后，由于成人生物体比初始受精卵更为复杂，因此需要大量的自组织（从较低水平过程中出现高水平模式）。几十年来，已经研究了数十年来的embryo构图。然而，盛行的理论难以解决实验操作过程中观察到的鲁棒性，可伸缩性和自组织，这表明与生物学现实的不匹配是严重的不匹配。在早期的果蝇（果蝇）胚胎中，这种不匹配尤为明显，这是一种重要的模型系统，这是一个更简单的模型，比大量的属性更广泛地研究，并且比大多数其他物种更广泛地研究了果糖。 The early stages of Drosophila's anteroposterior (head-to-tail) patterning are more robust than we can account for, even though we know the 15 genes involved, the 4 initial signals laid down by the embryo's mother that they respond to, and some of the regulatory interactions between these components.HYPOTHESISWe believe that the robustness of Drosophila patterning emerges from the structure of the whole early anteroposterior patterning network (the full 15个基因及其4个输入之间的一组调节相互作用）结合了以下事实：从这些基因中表达的mRNA和蛋白质分子在附近的核之间扩散。虽然早期果蝇胚胎中有成千上万个核，但直到放置最初的前后模式后，细胞膜才会形成。我们假设模式网络利用了核之间的空间相互作用，以在整个组织的水平上产生模式调节。这个想法与当前适用于果蝇胚胎的数学模型形成鲜明对比，该模型假设图案的输入将在本地解释（读取）。Obigntiveswe我们旨在解决模式网络的结构，并解释为什么它如此可靠地产生了一个近乎野生型（正常）Embryo模式的输出，即使在启动条件下也很强烈。然后，我们将使用对果蝇胚胎中图案的新理解来提取可用于了解其他动物胚胎中的发育模式的新一般原则，或者在类似胚胎的胚胎样结构中可以从干细胞中产生。我们将使用尖端的成像方法来揭示野生型和突变胚胎中的模式如何展开，然后使用计算模拟来了解基础基因网络如何通过解决胚胎发展的基本理解来解决我们对胚胎发展的基本理解，从而解决了长期和根本的问题。我们的发现将与发展生物学家（果蝇研究人员和研究其他动物系统的人）以及从理论角度研究模式的数学生物学家直接相关。我们发现的原理还将在合成和干细胞生物学方面具有实际应用，这有助于在发育疾病，再生和生物工程中的长期翻译应用。