Robust scaling and self-organisation of the Drosophila anteroposterior axis

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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.