WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids
- The Rockefeller University, United States
Abstract
Self-organization of discrete fates in human gastruloids is mediated by a hierarchy of signaling pathways. How these pathways are integrated in time, and whether cells maintain a memory of their signaling history remains obscure. Here, we dissect the temporal integration of two key pathways, WNT and ACTIVIN, which along with BMP control gastrulation. CRISPR/Cas9-engineered live reporters of SMAD1, 2 and 4 demonstrate that in contrast to the stable signaling by SMAD1, signaling and transcriptional response by SMAD2 is transient, and while necessary for pluripotency, it is insufficient for differentiation. Pre-exposure to WNT, however, endows cells with the competence to respond to graded levels of ACTIVIN, which induces differentiation without changing SMAD2 dynamics. This cellular memory of WNT signaling is necessary for ACTIVIN morphogen activity. A re-evaluation of the evidence gathered over decades in model systems, re-enforces our conclusions and points to an evolutionarily conserved mechanism.
Data availability
Sequencing data have been deposited in GEO under accession code GSE111717.
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WNT signaling memory is required for ACTIVIN to function as a morphogenPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE111717).
Article and author information
Author details
Funding
National Science Foundation (Graduate Research Fellowship DGE132526)
- Anna Yoney
National Institute of General Medical Sciences (Research Project R01GM101653)
- Eric D Siggia
- Ali H Brivanlou
Eunice Kennedy Shriver National Institute of Child Health and Human Development (Research Project R01HD080699)
- Eric D Siggia
- Ali H Brivanlou
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Lee L Rubin, Harvard Stem Cell Institute, Harvard University, United States
Publication history
- Received: May 11, 2018
- Accepted: October 11, 2018
- Accepted Manuscript published: October 12, 2018 (version 1)
- Version of Record published: November 13, 2018 (version 2)
Copyright
© 2018, Yoney et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids
eLife 7:e38279.
https://doi.org/10.7554/eLife.38279
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