Whole body regeneration deploys a rewired embryonic gene regulatory network logic

A long-held hypothesis in regeneration proposes that developmental processes are re-deployed during regeneration. To investigate this, we compared embryonic and regeneration gene regulatory networks (GRN) in the sea anemone Nematostella vectensis using transcriptomic time series spanning these two developmental trajectories. Here, we show that regeneration reuses cohorts of the embryonic genes along with a small set of genes whose expression dynamics are specific to regeneration. We identified co-expression modules that are either conserved between embryogenesis and regeneration or specific to regeneration, with the latter linked to cellular mechanisms such as apoptosis, tissue remodeling, and wound healing. Functional assays revealed that apoptosis and cWnt signaling pathways are partially MEK/ERK dependent, have largely distinct downstream targets but converge to coordinate regenerative responses. Collectively, these results indicate that regeneration in N. vectensis represents a partial redeployment and extensive rewiring of the embryonic GRN, reactivating developmental modules through a regeneration-specific network logic.