Division of labor between ERK/MAPK and Notch signaling in regulating distinct proliferative populations during jellyfish tentacle regeneration

Regeneration restores lost tissues through diverse cellular strategies that vary across species and tissue contexts. In many systems, regeneration involves blastema formation; however, how blastema formation is coordinated in tissues employing multiple stem/progenitor populations remains unclear. Here, we investigate tentacle regeneration in the hydrozoan jellyfish Cladonema, in which our previous work identified two distinct proliferative populations: resident homeostatic stem cells (RHSCs), which contribute to tissue production during homeostasis and regeneration, and repair-specific proliferative cells (RSPCs), which are transiently induced upon injury to form the blastema. While extensive cell death occurs shortly after injury, it is largely dispensable for blastema formation. Using pharmacological inhibition and cell proliferation analyses, we identify ERK/MAPK signaling as a key regulator of blastema formation. ERK/MAPK signaling is rapidly activated at the injury site and promotes proliferation of RSPCs. In contrast, inhibition of Notch signaling disrupts nematocyte differentiation and increases proliferative activity in RHSCs, indicating that Notch signaling governs the balance between differentiation and proliferation in RHSCs. Together, these findings reveal a division of labor between conserved signaling pathways in regulating distinct proliferative populations during tentacle regeneration.