Dynamic Image-Based Modelling of Kidney Branching Morphogenesis

TL;DR

This study uses dynamic imaging and modeling to explore kidney branching morphogenesis, suggesting a combined role of Turing patterns and geometry effects in branch point formation.

Contribution

It introduces a novel 2D movie-based modeling approach to test and support the hypothesis that Turing mechanisms and geometry effects jointly regulate kidney branching.

Findings

Turing patterns are sensitive to initial conditions on epithelial shapes.

A diffusion-dependent geometry effect reproduces growth fields well.

GDNF-RET interactions fit the Turing model for kidney branching.

Abstract

Kidney branching morphogenesis has been studied extensively, but the mechanism that defines the branch points is still elusive. Here we obtained a 2D movie of kidney branching morphogenesis in culture to test different models of branching morphogenesis with physiological growth dynamics. We carried out image segmentation and calculated the displacement fields between the frames. The models were subsequently solved on the 2D domain, that was extracted from the movie. We find that Turing patterns are sensitive to the initial conditions when solved on the epithelial shapes. A previously proposed diffusion-dependent geometry effect allowed us to reproduce the growth fields reasonably well, both for an inhibitor of branching that was produced in the epithelium, and for an inducer of branching that was produced in the mesenchyme. The latter could be represented by Glial-derived neurotrophic factor (GDNF), which is expressed in the mesenchyme and induces outgrowth of ureteric branches. Considering that the Turing model represents the interaction between the GDNF and its receptor RET very well and that the model reproduces the relevant expression patterns in developing wildtype and mutant kidneys, it is well possible that a combination of the Turing mechanism and the geometry effect control branching morphogenesis.