期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：35
DOI：10.1073/pnas.2204122119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Wnt signaling pathways are found exclusively in animal systems. They are of crucial importance for development, cell differentiation, and tumorigenesis. Wnt signaling pathways are also instrumental for regenerative processes from
Hydra to humans. Here we show that Wnt signaling is activated by default after an injury as a consequence of generic mitogen-activated protein kinase phosphorylation to drive tissues into a regeneration-competent state. Positional specification at later stages is achieved by a tissue-dependent sensitivity to the generic wound signals, which either allows or prevents the establishment of a persisting Wnt/β-catenin feedback loop and axis formation.
Hydra’s almost unlimited regenerative potential is based on Wnt signaling, but so far it is unknown how the injury stimulus is transmitted to discrete patterning fates in head and foot regenerates. We previously identified mitogen-activated protein kinases (MAPKs) among the earliest injury response molecules in
Hydra head regeneration. Here, we show that three MAPKs—p38, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases (ERKs)—are essential to initiate regeneration in
Hydra, independent of the wound position. Their activation occurs in response to any injury and requires calcium and reactive oxygen species (ROS) signaling. Phosphorylated MAPKs hereby exhibit cross talk with mutual antagonism between the ERK pathway and stress-induced MAPKs, orchestrating a balance between cell survival and apoptosis. Importantly,
Wnt3 and
Wnt9/10c, which are induced by MAPK signaling, can partially rescue regeneration in tissues treated with MAPK inhibitors. Also, foot regenerates can be reverted to form head tissue by a pharmacological increase of β-catenin signaling or the application of recombinant Wnts. We propose a model in which a β-catenin-based stable gradient of head-forming capacity along the primary body axis, by differentially integrating an indiscriminate injury response, determines the fate of the regenerating tissue. Hereby, Wnt signaling acquires sustained activation in the head regenerate, while it is transient in the presumptive foot tissue. Given the high level of evolutionary conservation of MAPKs and Wnts, we assume that this mechanism is deeply embedded in our genome.
