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dc.contributor.authorChhabra, Sapnaen_US
dc.contributor.authorLiu, Lizhongen_US
dc.contributor.authorGoh, Ryanen_US
dc.contributor.authorKong, Xiangyuen_US
dc.contributor.authorWarmflash, Aryehen_US
dc.coverage.spatialUnited Statesen_US
dc.date2019-09-23
dc.date.accessioned2020-04-08T16:12:37Z
dc.date.available2020-04-08T16:12:37Z
dc.date.issued2019-10
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/31613879
dc.identifier.citationSapna Chhabra, Lizhong Liu, Ryan Goh, Xiangyu Kong, Aryeh Warmflash. 2019. "Dissecting the dynamics of signaling events in the BMP, WNT, and NODAL cascade during self-organized fate patterning in human gastruloids.." PLoS Biol, Volume 17, Issue 10, e3000498. https://doi.org/10.1371/journal.pbio.3000498
dc.identifier.issn1545-7885
dc.identifier.urihttps://hdl.handle.net/2144/40054
dc.description.abstractDuring gastrulation, the pluripotent epiblast self-organizes into the 3 germ layers-endoderm, mesoderm and ectoderm, which eventually form the entire embryo. Decades of research in the mouse embryo have revealed that a signaling cascade involving the Bone Morphogenic Protein (BMP), WNT, and NODAL pathways is necessary for gastrulation. In vivo, WNT and NODAL ligands are expressed near the site of gastrulation in the posterior of the embryo, and knockout of these ligands leads to a failure to gastrulate. These data have led to the prevailing view that a signaling gradient in WNT and NODAL underlies patterning during gastrulation; however, the activities of these pathways in space and time have never been directly observed. In this study, we quantify BMP, WNT, and NODAL signaling dynamics in an in vitro model of human gastrulation. Our data suggest that BMP signaling initiates waves of WNT and NODAL signaling activity that move toward the colony center at a constant rate. Using a simple mathematical model, we show that this wave-like behavior is inconsistent with a reaction-diffusion-based Turing system, indicating that there is no stable signaling gradient of WNT/NODAL. Instead, the final signaling state is homogeneous, and spatial differences arise only from boundary effects. We further show that the durations of WNT and NODAL signaling control mesoderm differentiation, while the duration of BMP signaling controls differentiation of CDX2-positive extra-embryonic cells. The identity of these extra-embryonic cells has been controversial, and we use RNA sequencing (RNA-seq) to obtain their transcriptomes and show that they closely resemble human trophoblast cells in vivo. The domain of BMP signaling is identical to the domain of differentiation of these trophoblast-like cells; however, neither WNT nor NODAL forms a spatial pattern that maps directly to the mesodermal region, suggesting that mesoderm differentiation is controlled dynamically by the combinatorial effect of multiple signals. We synthesize our data into a mathematical model that accurately recapitulates signaling dynamics and predicts cell fate patterning upon chemical and physical perturbations. Taken together, our study shows that the dynamics of signaling events in the BMP, WNT, and NODAL cascade in the absence of a stable signaling gradient control fate patterning of human gastruloids.en_US
dc.description.sponsorshipR01 GM126122 - NIGMS NIH HHSen_US
dc.languageEnglish
dc.relation.ispartofPLoS Biology
dc.rights© 2019 Chhabra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are crediteden_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/.
dc.subjectBenzothiazolesen_US
dc.subjectBody patterningen_US
dc.subjectBone morphogenetic protein 4en_US
dc.subjectCell differentiationen_US
dc.subjectCell lineen_US
dc.subjectGastrulaen_US
dc.subjectGastrulationen_US
dc.subjectGene expression regulationen_US
dc.subjectHuman embryonic stem cellsen_US
dc.subjectHumansen_US
dc.subjectMesodermen_US
dc.subjectModels, biologicalen_US
dc.subjectModels, statisticalen_US
dc.subjectNodal proteinen_US
dc.subjectOrganoidsen_US
dc.subjectSignal transductionen_US
dc.subjectWnt proteinsen_US
dc.subjectBiological sciencesen_US
dc.subjectMedical and health sciencesen_US
dc.subjectAgricultural and veterinary sciencesen_US
dc.subjectDevelopmental biologyen_US
dc.titleDissecting the dynamics of signaling events in the BMP, WNT, and NODAL cascade during self-organized fate patterning in human gastruloids.en_US
dc.typeArticleen_US
dc.description.versionPublished versionen_US
dc.identifier.doi10.1371/journal.pbio.3000498
pubs.elements-sourcepubmeden_US
pubs.notesEmbargo: Not knownen_US
pubs.organisational-groupBoston Universityen_US
pubs.organisational-groupBoston University, College of Arts & Sciencesen_US
pubs.organisational-groupBoston University, College of Arts & Sciences, Department of Mathematics & Statisticsen_US
pubs.publication-statusPublished onlineen_US
dc.identifier.orcid0000-0003-3632-9978 (Goh, Ryan)
dc.identifier.mycv489888


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© 2019 Chhabra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Except where otherwise noted, this item's license is described as © 2019 Chhabra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited