How ERK helps zebrafish embryos grow a “thick skin”
Summary by Will Anderson: Ramkumar, N., Richardson, C., O'Brien, M., Butt, F. A., Park, J., Chao, A. T., Bagnat, M., Poss, K. D., & Di Talia, S. (2025). Phased ERK responsiveness and developmental robustness regulate teleost skin morphogenesis. Proc Natl Acad Sci U S A, 122(10), e2410430122. https://doi.org/10.1073/pnas.2410430122
Image credit: Wikimedia Commons (Azul)
Embryonic development is a complex and coordinated process that relies on a limited number of signaling inputs to create the tissues that compose adult organisms. Development must also be robust: growing organisms rarely experience perfect circumstances and must adapt to varying environmental, molecular, and genetic conditions. Here, Ramkumar et al. study live changes in the zebrafish periderm – the “skin” of the organism – as a model for the rapid growth, responsiveness to signals, and robustness of vertebrate tissues during development (Ramkumar et al., 2025).
As the embryonic axis quickly elongates during development, the surrounding periderm must respond with its own rapid growth. The authors first sought to understand how this peridermal change occurs at such a swift and reliable pace by live-imaging transgenic embryos with fluorescent periderm cells. They found that this rapid expansion is driven primarily by cell divisions oriented along the anterior-posterior axis. Further, by estimating cellular tension using images of these labeled cells, the authors determined that the physical stress experienced by the periderm is highest along its anterior-posterior axis, perhaps explaining the origin of these oriented divisions.
Next, the authors investigated the role of extracellular signal-regulated kinase (ERK), a known contributor to tissue growth, in peridermal expansion (Lavoie et al., 2020). To observe ERK signaling dynamics in real time, the group used a transgenic zebrafish line which expresses a fluorescent protein that translocates to the cytoplasm in response to the presence of ERK (Regot et al., 2014). Tracking peridermal cells during expansion and optogenetically manipulating ERK, they observed that high ERK activity is indeed associated with the cell division that drives the tissue’s growth. Next, the group used a transgenic line that reports the activity of cyclin-dependent kinase (CDK), a cell cycle marker, via the same translocation mechanism to observe the interplay of ERK signaling and cell division (Spencer et al., 2013). As development proceeds and ERK becomes more pulsatile, the group noticed an increase in cells experiencing high ERK in combination with low CDK. Not only is the ERK signal itself changing throughout development, but cells’ response to the same signal is changing: cells experiencing high ERK early in development are more likely to divide than cells experiencing the same signal later in development.
Having established that ERK-driven cellular division plays a role in peridermal expansion, Ramkumar et al. next sought to determine the extent to which cellular proliferation is required in this process. Using a transgenic zebrafish line whose periderm cells express the cell cycle inhibitor p21, they surprisingly observed that these embryos lacking proliferative capacity still developed into healthy adults with an intact periderm (Pu et al., 2020). This peridermal growth despite inhibited cell division was achieved by an increase in cell size: the authors found that periderm cells were ~4 times larger in these transgenic embryos compared to controls at ~48 hours post-fertilization. This extreme adaptation to molecular challenge highlights the robustness of developmental processes against perturbations.
Altogether, Ramkumar et al.’s exploration of the periderm’s developmental dynamics, relationship with ERK signaling, and resilience in the face of restrictive conditions provides a fascinating snapshot of the intricacy of vertebrate development.
References
Ramkumar, N., Richardson, C., O'Brien, M., Butt, F. A., Park, J., Chao, A. T., Bagnat, M., Poss, K. D., & Di Talia, S. (2025). Phased ERK responsiveness and developmental robustness regulate teleost skin morphogenesis. Proc Natl Acad Sci U S A, 122(10), e2410430122. https://doi.org/10.1073/pnas.2410430122
Lavoie, H., Gagnon, J., & Therrien, M. (2020). ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol, 21(10), 607-632. https://doi.org/10.1038/s41580-020-0255-7
Regot, S., Hughey, J. J., Bajar, B. T., Carrasco, S., & Covert, M. W. (2014). High-sensitivity measurements of multiple kinase activities in live single cells. Cell, 157(7), 1724-1734. https://doi.org/10.1016/j.cell.2014.04.039
Spencer, S. L., Cappell, S. D., Tsai, F. C., Overton, K. W., Wang, C. L., & Meyer, T. (2013). The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell, 155(2), 369-383. https://doi.org/10.1016/j.cell.2013.08.062
Pu, W., Han, X., He, L., Li, Y., Huang, X., Zhang, M., Lv, Z., Yu, W., Wang, Q. D., Cai, D., Wang, J., Sun, R., Fei, J., Ji, Y., Nie, Y., & Zhou, B. (2020). A genetic system for tissue-specific inhibition of cell proliferation. Development, 147(4). https://doi.org/10.1242/dev.183830