Long range signalling by morphogens and their inhibitors define embryonic patterning yet quantitative data and models are rare, especially in humans. Here we use a human embryonic stem cell micropattern system to model formation of the primitive streak (PS) by WNT. In the pluripotent state E-CADHERIN (E-CAD) transduces boundary forces to focus WNT signalling to colony border. Following application of WNT ligand, E-CAD mediates a front or wave of epithelial-to-mesenchymal (EMT) conversion analogous to PS extension in an embryo. By knocking out the secreted WNT inhibitors active in our system, we show that DKK1 alone controls the extent and duration of patterning. The NODAL inhibitor CERBERUS1 acts downstream of WNT to refine the endoderm versus mesoderm fate choice. Our EMT wave is a generic property of a bistable system with diffusion and a single quantitative model describes both the wave and our knockout data.
ACCEPTED MANUSCRIPT
RESEARCH ARTICLE|
01 January 2019
A wave of WNT signalling balanced by secreted inhibitors controls primitive streak formation in micropattern colonies of human embryonic stem cells
I. Martyn,
I. Martyn
1
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA
2
Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA
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A. H. Brivanlou,
A. H. Brivanlou
†
1
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA
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E. D. Siggia
E. D. Siggia
†
2
Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA
3
Lead Contact
Search for other works by this author on:
I. Martyn
1
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA
2
Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA
A. H. Brivanlou
†
1
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA
E. D. Siggia
†
2
Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA
3
Lead Contact
Received:
12 Oct 2018
Accepted:
20 Feb 2019
Online ISSN: 1477-9129
Print ISSN: 0950-1991
Funding
National Science Foundation
(Graduate Research Fellowship)
Foundation for the National Institutes of Health
(R01 HD080699)
Development dev.172791.
Article history
Received:
12 Oct 2018
Accepted:
20 Feb 2019
Currently Viewing Accepted Manuscript - Newer Version Available
25 Mar 2019
Citation
I. Martyn, A. H. Brivanlou, E. D. Siggia; A wave of WNT signalling balanced by secreted inhibitors controls primitive streak formation in micropattern colonies of human embryonic stem cells. Development 2019; dev.172791. doi: https://doi.org/10.1242/dev.172791
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