Mechanistic regulation of planarian shape during growth and degrowth.

Adult planarians can grow when fed and degrow (shrink) when starved while maintaining their whole-body shape. It is unknown how the morphogens patterning the planarian axes are coordinated during feeding and starvation or how they modulate the necessary differential tissue growth or degrowth. Here, we investigate the dynamics of planarian shape together with a theoretical study of the mechanisms regulating whole-body proportions and shape. We found that the planarian body proportions scale isometrically following similar linear rates during growth and degrowth, but that fed worms are significantly wider than starved worms. By combining a descriptive model of planarian shape and size with a mechanistic model of anterior-posterior and medio-lateral signaling calibrated with a novel parameter optimization methodology, we theoretically demonstrate that the feedback loop between these positional information signals and the shape they control can regulate the planarian whole-body shape during growth. Furthermore, the computational model produced the correct shape and size dynamics during degrowth as a result of a predicted increase in apoptosis rate and pole signal during starvation. These results offer mechanistic insights into the dynamic regulation of whole-body morphologies.

Continuous Dynamic Modeling of Regulated Cell Adhesion: Sorting, Intercalation, and Involution.

Cell-cell adhesion is essential for tissue growth and multicellular pattern formation and crucial for the cellular dynamics during embryogenesis and cancer progression. Understanding the dynamical gene regulation of cell adhesion molecules (CAMs) responsible for the emerging spatial tissue behaviors is a current challenge because of the complexity of these nonlinear interactions and feedback loops at different levels of abstraction-from genetic regulation to whole-organism shape formation. To extend our understanding of cell and tissue behaviors due to the regulation of adhesion molecules, here we present a novel, to our knowledge, model for the spatial dynamics of cellular patterning, growth, and shape formation due to the differential expression of CAMs and their regulation. Capturing the dynamic interplay between genetic regulation, CAM expression, and differential cell adhesion, the proposed continuous model can explain the complex and emergent spatial behaviors of cell populations that change their adhesion properties dynamically because of inter- and intracellular genetic regulation. This approach can demonstrate the mechanisms responsible for classical cell-sorting behaviors, cell intercalation in proliferating populations, and the involution of germ layer cells induced by a diffusing morphogen during gastrulation. The model makes predictions on the physical parameters controlling the amplitude and wavelength of a cellular intercalation interface, as well as the crucial role of N-cadherin regulation for the involution and migration of cells beyond the gradient of the morphogen Nodal during zebrafish gastrulation. Integrating the emergent spatial tissue behaviors with the regulation of genes responsible for essential cellular properties such as adhesion will pave the way toward understanding the genetic regulation of large-scale complex patterns and shapes formation in developmental, regenerative, and cancer biology.

Computational Systems Biology of Morphogenesis.

Extracting mechanistic knowledge from the spatial and temporal phenotypes of morphogenesis is a current challenge due to the complexity of biological regulation and their feedback loops. Furthermore, these regulatory interactions are also linked to the biophysical forces that shape a developing tissue, creating complex interactions responsible for emergent patterns and forms. Here we show how a computational systems biology approach can aid in the understanding of morphogenesis from a mechanistic perspective. This methodology integrates the modeling of tissues and whole-embryos with dynamical systems, the reverse engineering of parameters or even whole equations with machine learning, and the generation of precise computational predictions that can be tested at the bench. To implement and perform the computational steps in the methodology, we present user-friendly tools, computer code, and guidelines. The principles of this methodology are general and can be adapted to other model organisms to extract mechanistic knowledge of their morphogenesis.