Epithelial tissue folding as a morphogenetic tool

• Applicants: Dr. Natalie Dye; Dr. Marko Popovic
• Subject Area: Biophysics ; Developmental Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544201605

How an animal tissue grows into its final form remains a fundamental open question in biology. Although much is known about the biochemical signaling pathways regulating growth, the mechanics involved in shaping tissues during growth are less clear. This proposal examines a mechanism by which actively generated mechanical stresses shape a growing epithelial tissue. Specifically, we examine how an initially flat epithelial tissue can use folding as a morphogenetic tool. We propose that a fold can serve as an active tissue boundary influencing the direction and remodeling of the surrounding tissue. Furthermore, we propose that a fold can store tissue material and possibly mechanical stress to be deployed at a later time in a pre-patterned fashion. Such transient tissue folding would constitute a novel morphogenetic mechanism whereby the orientation of tissue growth and remodeling is organized by folds at the boundary. We use the developing fruit fly wing as a model epithelium, which grows during the larval stages of the fly’s life cycle before undergoing further remodeling at pupal stages. During its growth, the wing tissue develops deep folds that coincide with the orientation of anisotropic growth in the region surrounded by the folds. Thereafter, these folds unfold as the tissue reshapes itself into a bilayered epithelium. Although initial fold formation has been studied, it remains unclear what is the physical mechanism that underlies stable growth of the folds and what determines their morphology. Furthermore, it is unknown whether folds actively pull on the surrounding tissue or whether the deepening of the folds is a consequence of activity in the surrounding tissue. To investigate this phenomenon, we have developed a highly collaborative work program, involving tightly interconnected experimental and theoretical approaches. First, we focus on the folds, seeking to understand the process of tissue folding and subsequent unfolding. We will use modern microscopy methods to generate 3D reconstructions of the entire developing wing tissue at timepoints over its 2 days of larval growth to quantitatively analyze fold geometry. In parallel, we will develop a model of tissue folding to relate the observed fold geometries with specific folding mechanisms and tissue properties. We will then use genetic perturbations to generate ectopic folds to test our models. In the second part, we will investigate the bidirectional mechanical interplay between folds and the surrounding tissue. We will examine tissue flow around the folds and test whether an ectopic fold is sufficient to reorient growth of the surroundings. We will also develop continuum models of tissue flow near a fold and numerical simulations of the overall fold-tissue system mechanics that will provide testable predictions of tissue and fold properties. In summary, this project employs an interdisciplinary approach to examine transient tissue folding as a morphogenetic tool.

• DFG Programme: Research Grants