Mouse embryo geometry drives formation of robust signaling gradients through receptor localization

Zhang, Zhechun; Zwick, Steven; Loew, Ethan; Grimley, Joshua S.; Ramanathan, Sharad

doi:10.1038/s41467-019-12533-7

Cited by 61 publications

(64 citation statements)

References 55 publications

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“…Negative feedback by NOG, which is directly induced by BMP4, is also required to explain the fate patterning ( Etoc et al, 2016 ). Interestingly, a recent report has shown that BMP receptors are basolaterally localised in the early post-implantation mouse epiblast, and this is required for the formation of a robust BMP signalling gradient ( Zhang et al, 2019 ), indicating tissue geometry controls pluripotent cell differentiation both in mice and humans ( Fig. 4 ).…”

Section: Gastrulation: From Pluripotency Loss To Lineage Specificatiomentioning

confidence: 99%

Mechanisms of human embryo development: from cell fate to tissue shape and back

2020

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Gene regulatory networks and tissue morphogenetic events drive the emergence of shape and function: the pillars of embryo development. Although model systems offer a window into the molecular biology of cell fate and tissue shape, mechanistic studies of our own development have so far been technically and ethically challenging. However, recent technical developments provide the tools to describe, manipulate and mimic human embryos in a dish, thus opening a new avenue to exploring human development. Here, I discuss the evidence that supports a role for the crosstalk between cell fate and tissue shape during early human embryogenesis. This is a critical developmental period, when the body plan is laid out and many pregnancies fail. Dissecting the basic mechanisms that coordinate cell fate and tissue shape will generate an integrated understanding of early embryogenesis and new strategies for therapeutic intervention in early pregnancy loss.

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Section: Gastrulation: From Pluripotency Loss To Lineage Specificatiomentioning

confidence: 99%

Mechanisms of human embryo development: from cell fate to tissue shape and back

2020

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“…Altogether, these observations suggest that one role of the extraembryonic ectoderm is to bias the spontaneous symmetry breaking event and that the epithelial organization of the EPI contributes to this by raising the threshold for signal response. The mechanism for this is unclear at the moment but the junctional organization of signaling receptors in the epiblast 48,49 is likely to play a role. The situation we observe in EpiTS embryoid phenocopies aspects of the activity of the AVE where BMP, TGF-β and WNT signaling inhibitors secreted from the Anterior Visceral Endoderm (AVE) inhibit the spread of T/Bra expression, contributing to the anterior-posterior patterning of the embryo, suggesting that the epithelial organization of the epiblast contributes to this effect.…”

Section: The Controlled Interaction Between Epi and Tsc Aggregates Lementioning

confidence: 99%

Bioengineered embryoids mimic post-implantation development in vitro

Girgin

Broguière

Hoehnel³

et al. 2021

Preprint

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The difficulty of studying post-implantation development in mammals has sparked a flurry of activity to develop in vitro models, termed embryoids, based on self-organizing pluripotent stem cells. Previous approaches to derive embryoids either lack the physiological morphology and signaling interactions, or are not yet optimal for modeling post-gastrulation development. Here, we report a bioengineering-inspired approach aimed at addressing this gap. A high-throughput cell aggregation approach was employed to simultaneously coax mouse embryonic stem cells (ESCs) into hundreds of uniform epiblast-like (EPI) aggregates in a solid matrix-free manner. When co-cultured with mouse trophoblast stem cell (TSC) aggregates, the resulting hybrid structures initiate gastrulation-like events and undergo axial morphogenesis to yield structures, termed EpiTS embryoids, with a pronounced anterior development, including brain-like regions. We identify the presence of an epithelium in EPI aggregates as the major determinant for the axial morphogenesis and anterior development seen in EpiTS embryoids. Our results demonstrate the potential of EpiTS embryoids to study peri-gastrulation development in vitro.

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“…We conducted our experiments using WA01 (H1) human embryonic stem cells. We also used an H1 cell line in which both OCT4 and SOX2 were tagged with fluorescent proteins as previously described 11 . In these cells, one endogenous copy of OCT4 was replaced with OCT4:tdTomato followed by an internal ribosomal entry site and a neomycin resistance gene to allow for selection, and one endogenous copy of SOX2 was replaced with SOX2:FLAG:Citrine:P2A:PuroR.…”

Section: Cell Linesmentioning

confidence: 99%

“…We chose this substrate to allow all cells to receive the BMP and Activin/NODAL signals we added to the media. TGF-β superfamily receptors, such as those for BMP4 and Activin A, are localized basolaterally in epithelial stem cell colonies and in vivo in the epiblast, so they are insulated from ligands in the apical media or luminal fluid 10,11 . Typical tissue culture conditions allow for only the cells on the edge of the colony to receive signals, but growing cells on a membrane allows all cells in a colony access to the BMP and Activin ligands.…”

Section: Cell Culturementioning

confidence: 99%

“…We demonstrated that the developmental trajectories of hESCs in OCT4 and SOX2 space were predictive of the germ layer fate choice of cells, and they allowed such prediction days before the expression of classical master regulators of these fates. To show this, we employed our validated hESC line in which one allele each of OCT4 and SOX2 had been replaced with OCT4:RFP and SOX2:YFP, respectively, at the endogenous locus 11 (Figure S2A-C). Using flow cytometry, we could follow the developmental trajectories of a population of hESCs (with high levels of OCT4 and SOX2) into ectodermal progenitors over the course of six days as they downregulated OCT4.…”

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confidence: 99%

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Changing the Waddington landscape to control mesendoderm competence

Valcourt

Huang

Kundu

et al. 2019

Preprint

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19As pluripotent human embryonic stem cells progress towards one germ layer fate, they lose the 20 ability to adopt alternative fates. It is unknown how the cells' competence for these alternative 21 fates changes along their developmental trajectory or if this competence can be modulated. Here, 22 we show that a differentiating stem cell's probability of adopting a mesendodermal fate when 23 given the appropriate signal falls sharply at a specific point along the ectodermal trajectory, and 24 we further demonstrate that this point can be moved using genetic perturbations. Using a low-25 dimensional reaction coordinate to monitor progression towards ectoderm, we can determine the 26 probability that individual cells at different points along this path can transition to the 27 2 mesendodermal fate upon BMP4 and Activin A signal exposure. Knowing this probability allows 28 us to prospectively isolate and profile differentiating cells based on their mesendoderm 29 competence. Analysis and validation of these RNA-seq and ATAC-seq profiles identified 30 transcription factors that can independently control the cell's mesendoderm competence and its 31 progression along the ectodermal developmental trajectory. In the classical picture of a 32 Waddington landscape, these effects correspond to altering the barrier between fates and changing 33 the cell's location on the landscape, respectively. The ability of the underlying gene regulatory 34 network to modulate these two aspects of the developmental landscape could allow separate 35 control of the dynamics of differentiation and tissue size proportions. 36Main 37 Pluripotent cells have the ability to produce any of the myriad cell types seen in the adult body 1 , 38 but they lose this potential as they differentiate. During initial lineage specification, cells can 39 change their fate choice upon exposure to signals that induce an alternative selection 1-4 , such as 40 by transplantation to a different location in the embryo. In time, however, the cell's fate becomes 41 determined, and it is no longer competent to choose a different lineage in response to the same 42 external signals 5-7 . While lineage specification is relatively well-understood 8-17 , whether and how 43 competence for adopting alternative lineages can be tuned during differentiation is not. 44Determining how this competence is set and modulated is essential for understanding 45 developmental patterning and plasticity. 46There is a fundamental challenge in understanding the competence of a cell to choose a specific 47 Figure 1: Stem cells lose competence to adopt mesendodermal fates upon BMP4 and ActivinA signal exposure with increasing duration of Activin/NODAL inhibition. a, Schematic of a Waddington landscape illustrating the ectoderm (blue) / mesendoderm (yellow) fate choice. In this picture, the competence of a cell to produce mesendoderm depends both on the cell's location along the ectodermal developmental trajectory and on the position of the barrier between the ectoderm and mesendoderm fates...

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Mouse embryo geometry drives formation of robust signaling gradients through receptor localization

Cited by 61 publications

References 55 publications

Mechanisms of human embryo development: from cell fate to tissue shape and back

Mechanisms of human embryo development: from cell fate to tissue shape and back

Bioengineered embryoids mimic post-implantation development in vitro

Changing the Waddington landscape to control mesendoderm competence

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