Li Linlin, Mdluli Thembi, Buzzard Gregery, Umulis David
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, United States.
US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Comput Struct Biotechnol J. 2025 Aug 20;27:3729-3741. doi: 10.1016/j.csbj.2025.08.021. eCollection 2025.
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, , 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 and zebrafish through changes in expression only. We used multi-objective optimization to simultaneously fit a single core model to 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 variation in a small subset of parameters-particularly diffusion-related rates-can reconcile the experimentally measured BMP gradients in both species under wild-type conditions, whereas fitting both WT and mutant conditions requires additional species-specific regulatory extensions beyond the core model. This approach, involving simulation and multispecies optimization, provides a systematic method to explore the minimal parametric variations needed to account for interspecies differences in a developmental pathway. Rather than making predictive claims, our finding offers a framework for improving the interpretability and translational relevance of cross-species models.
空间分布的、不均匀的形态发生素梯度在整个动物界发育过程中的组织形成中起着至关重要的作用。骨形态发生蛋白（BMP）信号通路是一种在背腹（D-V）轴模式形成中被充分研究的形态发生素，已在斑马鱼等生物中得到广泛研究。鉴于该信号通路在形式和功能上都高度保守，我们试图确定一个限制拓扑结构和生物物理参数的核心数学模型是否仅通过表达变化就能完全重现小鼠和斑马鱼中观察到的梯度形成动态。我们使用多目标优化将单个核心模型同时拟合到小鼠和斑马鱼的数据及条件。通过探索具有不同参数的单个模型，我们确定了BMP信号通路的同源性和多样性。我们发现，一小部分参数（特别是与扩散相关的速率）的变化可以协调野生型条件下两个物种实验测量的BMP梯度，而拟合野生型和突变型条件则需要核心模型之外的其他物种特异性调控扩展。这种涉及模拟和多物种优化的方法提供了一种系统的方法，来探索解释发育途径中物种间差异所需的最小参数变化。我们的发现并非做出预测性声明，而是提供了一个框架，以提高跨物种模型的可解释性和转化相关性。
