Basement Membrane Guided Morphogenesis in vivo and in vitro

Morphogenesis is the process that generates 3-dimensional tissue and organ shape. Proper morphology is essential for organ functionality and defects in morphogenesis are linked to developmental disorders and disease. I propose that the basement membrane (BM) is a major geometric constraint for epithelial growth that instructs 3D morphogenesis according to the laws of mechanics. I have shown that differences in BM and epithelial growth lead to accumulation of growth-induced residual stress and elastic deformation, and that these forces mould 3D shape changes. I hypothesise here that growing epithelia dynamically fine-tune BM properties and growth to modulate their mechanical environment, and that BM mechanics feedback on 3D tissue shape and growth termination. I will employ a combination of advanced imaging, quantitative biophysical methods, genetic perturbations and modelling to investigate shared principles across fly, zebrafish and mammalian organoid systems. These cross- scale analyses will provide unprecedented biophysical characterisation of BM structure and the cellular regulation thereof, integrated with a mechanistic description of shape generation by cell-BM mechanics. Understanding the dynamic interplay between cells and their BM will provide new insight into developmental malformations and disease, and in addition will be instrumental for reverse engineering custom BMs in synthetic tissue and organ systems.