MAPK signaling links the injury response to Wnt-regulated patterning in Hydra regeneration

Hydra has a long history as an informative model to study pattern formation and regeneration. Wnt signaling is a critical component of Hydra patterning that must be activated during regeneration, but it is largely unknown how the injury stimulus ultimately leads to this activation. In a proteomic screen we previously identified mitogen protein kinases (MAPKs) among the earliest injury response factors in Hydra regeneration, making them attractive candidates to transmit injury-response signals to the initial steps of patterning, which in Hydra includes Wnt signaling. Our data demonstrate that three MAPKs, p38, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases (ERK), are essential to initiate regeneration in Hydra. This activation occurs in response to an injury signal, which consists of calcium and reactive oxygen species (ROS) signaling. Phosphorylated MAPKs exhibit cross-talk with a mutual antagonism between the ERK1/2 pathway and the stress induced MAPKs. The activation of these MAPK pathways, as well as the induction of apoptosis, occurs in all injuries regardless of the position of the wound. MAPK phosphorylation is required for the transcriptional activation of position independent Wnt3 and Wnt9/10c ligands. In summary, our data show that the activation of MAPKs is an essential component of the wound response which transmits the injury signal to induce the transcriptional activation of Wnt ligands, which are essential for patterning the regenerating tissue. Given the high level of evolutionary conservation of MAPKs and Wnts in the injury response, this likely represents a deeply conserved pathway in animals.