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.

背景成年生物体包含许多不同类型的细胞，它们被组织成复杂但有序的排列。胚胎模式是发育生物学的一个领域，研究这种复杂的排列是如何产生的。胚胎模式通常是健壮的，即使输入和条件不同，也能产生可靠的输出。它可以缩放(与胚胎大小成比例地调整)，例如在双胞胎生产期间。最后，它需要大量的自组织(从较低水平的过程中出现高水平的模式)，因为成年有机体比最初受精的鸡蛋要复杂得多。胚胎模式的研究已经有几十年了，使用的是“模型有机体”实验和数学理论的混合。然而，主流理论很难解释在实验操作中观察到的健壮性、可伸缩性和自组织，这表明与生物现实严重不匹配。这种不匹配在早期果蝇(果蝇)胚胎中尤为明显，这是一个重要的模型系统，比大多数其他物种更简单、更广泛地被研究，并且更有利于基因实验。果蝇前后(从头到尾)模式的早期阶段比我们所能解释的更强大，即使我们知道涉及的15个基因，它们所响应的胚胎母亲制定的4个初始信号，以及这些组件之间的一些调控相互作用。我们认为，果蝇模式的健壮性来自整个早期前后模式网络的结构(15个基因和它们的4个输入之间的全套调控相互作用)，以及从这些基因表达的mRNA和蛋白质分子在附近的细胞核之间扩散的事实。虽然在早期果蝇胚胎中有数千个细胞核，但它们之间的细胞膜直到最初的前后模式奠定后才形成。我们假设图案网络利用细胞核之间的空间相互作用在整个组织水平上产生图案调节；这一想法与目前应用于果蝇胚胎的数学模型形成对比，后者假设图案网络的输入将被局部解释(读出)。目的我们的目标是解析图案网络的结构，并解释为什么即使胚胎中的起始条件被相当强烈的扰动，它也如此可靠地产生接近野生型(正常)胚胎模式的输出。然后，我们将使用这种对果蝇胚胎模式的新理解来提取新的一般原理，这些原理可以用于理解其他动物胚胎或现在可以从干细胞产生的合成胚胎样结构中的发育模式。APPROACH是一项结合了显微镜、遗传学和数学建模的跨学科建议。我们将使用尖端成像方法来揭示野生型和突变胚胎中的模式是如何展开的，然后使用计算模拟来理解这些行为是如何由潜在的基因网络产生的。潜在的应用和BENEFITS他们的工作将通过解决一个长期存在的基本问题来促进我们对胚胎发育的基本理解。我们的发现将与发育生物学家(包括果蝇研究人员和那些研究其他动物系统的人)以及从理论角度研究图案的数学生物学家直接相关。我们发现的原理也将在合成和干细胞生物学中有实际应用，有助于在发育疾病、再生和生物工程中的长期翻译应用。