Mechanisms of symmetry breaking at molecular and cellular scales in planar polarity

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.