Modeling Key Genetic Pathways in Axolotl Limb Regeneration

Axolotls exhibit exceptional limb regenerative capacity. However, the coordinated molecular dynamics underlying this process has been incompletely understood. This study examines whether a quantitative modeling framework may reproduce the temporal interactions of core signaling pathways during axolotl limb regeneration. With publicly available datasets of stage-resolved gene-expression, this study has generated ordinary differential equation (ODE) and Boolean network models to simulate the dynamics of key regenerative pathways, such as FGF, Wnt, BMP, and TGF-β. Model outputs were compared with empirical expression trends and tested in pathway perturbations. According to simulated trajectories, a strong agreement with observed gene-expression patterns has been shown, along with Pearson correlation coefficients that exceeded 0.8 for main regulatory genes. Perturbation simulations indicated that 50% reductions in FGF or Wnt activity greatly decreased regenerative progression, while shifting the Boolean network toward non-regenerative attractor states. Early activation of FGF and Wnt was correlated with blastema initiation. However, later BMP and TGF-β actively corresponded to tissue outgrowth. These findings in this study suggest that coordinated feedback among core pathways may be critical for successful regeneration. In addition, a quantitative modeling framework may capture essential regenerative dynamics. This framework provides a quantitative foundation for future research in experimentation and comparison of vertebrate regeneration.