Associated organisationsUniversity of Oxford · University of SheffieldEurope PMC affiliations are not treated as award recipients or mapped locations.
Funding£3.7M
PeriodJan 2025 — Dec 2030
In plain English
AI plain-English summary
A fly’s wing cell decides which end is front and which is back, and a team of researchers wants to know how that decision happens at the level of individual molecules. This matters because the same molecular machinery that orients hairs on insect wings also guides how human organs form and heal. When this symmetry-breaking process goes wrong in people, it can lead to kidney cysts, neural tube defects, and hearing loss. The researchers will use advanced light and electron cryo-microscopy to watch how a handful of proteins—including Frizzled, Flamingo, and Van Gogh—assemble into asymmetric clusters on cell surfaces, then sort themselves to opposite ends of each cell. The project is fundamental science. It asks how a cell knows left from right, a question with no immediate medical application. But understanding these organising principles could eventually help tissue engineers build structures that mimic the body’s own polarity, such as kidney tubules or inner-ear hair cells that must all point in the same direction to function. Past discoveries in planar polarity have already revealed how organs coordinate their shape during development—deeper molecular knowledge may unlock ways to recreate that order in the lab.
View original technical description
Symmetry breaking in biological systems is fundamental for pattern formation and elaboration of organismal complexity. In this proposal we seek multi-scale understanding of the symmetry breaking that establishes planar polarity in animal tissues. We will combine our expertise—harnessing recent progress in molecular, cellular and genetic studies of planar polarity, as well as technological advances in light and electron cryo-microscopy/tomography—to dissect the mechanisms of symmetry breaking operating at molecular, cellular and tissue levels. Specifically, we will study the molecular basis of action for the highly conserved ‘core’ planar polarity pathway. Key components (Drosophila/mammal) include Fmi/Celsr adhesion GPCRs, Fz/Fzd family sevenpass transmembrane receptors, the fourpass Stbm/Vangl transmembrane proteins and the cytoplasmic proteins Dsh/Dvl, Pk/Prickle and Dgo/ANKRD6. We will ask: (i) how Fz and Fmi act together to break molecular symmetry and form asymmetric intercellular complexes (ii) how Fmi trans-activation occurs to trigger Stbm recruitment into asymmetric complexes (iii) how complexes assemble into stable clusters (iv) how complexes are molecularly sorted to break cellular symmetry and generate tissue-level planar polarity This work will provide insights into the molecular mechanisms of planar polarity and cell signalling, revealing fundamental organising principles that have the potential to advance tissue engineering and regenerative medicine.
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