WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/38279 |
| _version_ | 1818023925257338880 |
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| author | Anna Yoney Fred Etoc Albert Ruzo Thomas Carroll Jakob J Metzger Iain Martyn Shu Li Christoph Kirst Eric D Siggia Ali H Brivanlou |
| author_facet | Anna Yoney Fred Etoc Albert Ruzo Thomas Carroll Jakob J Metzger Iain Martyn Shu Li Christoph Kirst Eric D Siggia Ali H Brivanlou |
| author_sort | Anna Yoney |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T03:52:04Z |
| format | Article |
| id | doaj.art-f63cd96773234a5c94c1350230c6fbcc |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T03:52:04Z |
| publishDate | 2018-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f63cd96773234a5c94c1350230c6fbcc2022-12-22T02:03:14ZengeLife Sciences Publications LtdeLife2050-084X2018-10-01710.7554/eLife.38279WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloidsAnna Yoney0https://orcid.org/0000-0003-4988-9237Fred Etoc1Albert Ruzo2Thomas Carroll3Jakob J Metzger4Iain Martyn5Shu Li6Christoph Kirst7https://orcid.org/0000-0003-4867-5288Eric D Siggia8https://orcid.org/0000-0001-7482-1854Ali H Brivanlou9https://orcid.org/0000-0002-1761-280XLaboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, United States; Center for Studies in Physics and Biology, The Rockefeller University, New York, United StatesLaboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, United States; Center for Studies in Physics and Biology, The Rockefeller University, New York, United StatesLaboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, United StatesBioinformatics Resource Center, The Rockefeller University, New York, United StatesLaboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, United States; Center for Studies in Physics and Biology, The Rockefeller University, New York, United StatesLaboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, United States; Center for Studies in Physics and Biology, The Rockefeller University, New York, United StatesLaboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, United StatesCenter for Studies in Physics and Biology, The Rockefeller University, New York, United StatesCenter for Studies in Physics and Biology, The Rockefeller University, New York, United StatesLaboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, United StatesSelf-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.https://elifesciences.org/articles/38279Pluripotent stem cellsmesendoderm differentiationmicropatternsSMAD signalinglive imagingWNT |
| spellingShingle | Anna Yoney Fred Etoc Albert Ruzo Thomas Carroll Jakob J Metzger Iain Martyn Shu Li Christoph Kirst Eric D Siggia Ali H Brivanlou WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids eLife Pluripotent stem cells mesendoderm differentiation micropatterns SMAD signaling live imaging WNT |
| title | WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids |
| title_full | WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids |
| title_fullStr | WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids |
| title_full_unstemmed | WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids |
| title_short | WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids |
| title_sort | wnt signaling memory is required for activin to function as a morphogen in human gastruloids |
| topic | Pluripotent stem cells mesendoderm differentiation micropatterns SMAD signaling live imaging WNT |
| url | https://elifesciences.org/articles/38279 |
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