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| Item Type: | Article |
|---|---|
| Title: | WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids |
| Creators Name: | Yoney, A. and Etoc, F. and Ruzo, A. and Carroll, T. and Metzger, J.J. and Martyn, I. and Li, S. and Kirst, C. and Siggia, E.D. and Brivanlou, A.H. |
| 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. |
| Keywords: | Activins, Base Sequence, Bone Morphogenetic Proteins, Cell Differentiation, Endoderm, Gastrulation, Genetic Transcription, Mesoderm, Nucleotide Motifs, Pluripotent Stem Cells, Reporter Genes, Smad Proteins, Transforming Growth Factor beta, Wnt Signaling Pathway, Animals, Mice, Rats |
| Source: | eLife |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications |
| Volume: | 7 |
| Page Range: | e3827 |
| Date: | 13 November 2018 |
| Official Publication: | https://doi.org/10.7554/eLife.38279.001 |
| PubMed: | View item in PubMed |
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