Digital Cousins: Simultaneous Optimization of One Model for BMP Signaling in Distant Relatives Reveals Essential Core

Spatially distributed, nonuniform morphogen gradients play a crucial role in tissue organization during development across the animal kingdom. The Bone Morphogenetic Protein (BMP) pathway, a well-studied morphogen involved in dorsal-ventral (D-V) axis patterning, has been extensively studied in zebrafish, Drosophila , and other organisms. Given that this pathway is highly conserved in both form and function, we sought to determine whether a core mathematical model that constrained topology and biophysical parameters could fully reproduce the observed dynamics of gradient formation in both Drosophila and zebrafish through changes in expression only. We used multi-objective optimization to simultaneously fit a single core model to Drosophila and zebrafish data and conditions. By exploring a single model with varied parameters, we identified both the homology and diversification of the BMP pathway. We find that a core model with only two parametric changes could simultaneously replicate the experimentally measured BMP gradients in both species. This approach, involving simulation and multispecies optimization, provides a rigorous method to identify the minimum parameter adjustments needed for the measurement and simulation of one species to have predictive power in another system. The process offers a framework for enhancing cross-species predictions and improving the utility of preclinical animal models.