Edited by Ali H. Brivanlou, The Rockefeller University, New York, NY, and accepted by Editorial Board Member Brigid L. Hogan January 23, 2019 (received for review September 5, 2018)
While the dynamics of cellular signaling pathways have received increased attention recently, whether the dynamics of signaling vary depending on the context remains unclear. The WNT/β-catenin signaling pathway plays essential roles in embryonic development, control of cell proliferation, and maintenance of stem cell niches. Here we used quantitative microscopy to study the dynamics of the WNT pathway in pluripotent stem cells. Signaling dynamics were transient in the pluripotent state but sustained during differentiation, and this switch relied on synergy with other key developmental pathways. In addition, we show that β-catenin dynamics vary across several commonly used cell lines. This work highlights the changing dynamics of WNT signaling during early differentiation and provides a template for studying how signaling depends on cellular context.
WNT/β-catenin signaling is crucial to all stages of life. It controls early morphogenetic events in embryos, maintains stem cell niches in adults, and is dysregulated in many types of cancer. Despite its ubiquity, little is known about the dynamics of signal transduction or whether it varies across contexts. Here we probe the dynamics of signaling by monitoring nuclear accumulation of β-catenin, the primary transducer of canonical WNT signals, using quantitative live cell imaging. We show that β-catenin signaling responds adaptively to constant WNT signaling in pluripotent stem cells, and that these dynamics become sustained on differentiation. Varying dynamics were also observed in the response to WNT in commonly used mammalian cell lines. Signal attenuation in pluripotent cells is observed even at saturating doses, where ligand stability does not affect the dynamics. TGFβ superfamily ligands Activin and BMP, which coordinate with WNT signaling to pattern the gastrula, increase the β-catenin response in a manner independent of their ability to induce new WNT ligand production. Our results reveal how variables external to the pathway, including differentiation status and cross-talk with other pathways, dramatically alter WNT/β-catenin dynamics.
↵1Present address: Sainsbury Laboratory, Cambridge University, Cambridge CB2 1LR, United Kingdom.
↵2Present address: Centers for Disease Control and Prevention, Atlanta, GA 30333.
Author contributions: J.M. and A.W. designed research; J.M., Y.L., O.A., T.S., and M.S. performed research; M.S. contributed new reagents/analytic tools; J.M. and A.W. analyzed data; and J.M. and A.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. A.H.B. is a guest editor invited by the Editorial Board.
Data deposition: The analysis code for this study has been deposited in GitHub, https://github.com/josephkm.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1815363116/-/DCSupplemental.
Published under the PNAS license.
