On folding morphogenesis, a mechanical problem.

Tissue folding is a fundamental process that sculpts a simple flat epithelium into a complex three-dimensional organ structure. Whether it is the folding of the brain, or the looping of the gut, it has become clear that to generate an invagination or a fold of any form, mechanical asymmetries must exist in the epithelium. These mechanical asymmetries can be generated locally, involving just the invaginating cells and their immediate neighbours, or on a more global tissue-wide scale. Here, we review the different mechanical mechanisms that epithelia have adopted to generate folds, and how the use of precisely defined mathematical models has helped decipher which mechanisms are the key driving forces in different epithelia. This article is part of a discussion meeting issue 'Contemporary morphogenesis'.

Planar Differential Growth Rates Initiate Precise Fold Positions in Complex Epithelia.

Tissue folding is a fundamental process that shapes epithelia into complex 3D organs. The initial positioning of folds is the foundation for the emergence of correct tissue morphology. Mechanisms forming individual folds have been studied, but the precise positioning of folds in complex, multi-folded epithelia is less well-understood. We present a computational model of morphogenesis, encompassing local differential growth and tissue mechanics, to investigate tissue fold positioning. We use the Drosophila wing disc as our model system and show that there is spatial-temporal heterogeneity in its planar growth rates. This differential growth, especially at the early stages of development, is the main driver for fold positioning. Increased apical layer stiffness and confinement by the basement membrane drive fold formation but influence positioning to a lesser degree. The model successfully predicts the in vivo morphology of overgrowth clones and wingless mutants via perturbations solely on planar differential growth in silico.