Self-organization of a human organizer by combined Wnt and Nodal signalling

Martyn, Iain; Kanno, Tatiane Yumi Nakamura; Ruzo, Albert; Siggia, Eric D.; Brivanlou, Ali H.

doi:10.1038/s41586-018-0150-y

Cited by 245 publications

(266 citation statements)

References 21 publications

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“…Prolonged BMP signaling at the colony edge leads to differentiation towards an extra-embryonic fate (17). In response to BMP treatment, hESCs activate paracrine WNT and NODAL signaling, which are both necessary for mesendodermal ring formation (5,18). In contrast to BMP signaling, NODAL signaling activity is highly dynamic: a wave of signaling moves from the edge towards the colony center at a constant rate, specifying the mesendodermal rings in its wake ((15), Figure S1E).…”

Section: Introductionmentioning

confidence: 99%

Dissecting the dynamics of signaling events in the BMP, WNT, and NODAL cascade during self-organized fate patterning in human gastruloids

Chhabra

Liu

Goh

et al. 2018

Preprint

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During gastrulation, the pluripotent epiblast is patterned into the three germ layers, which form the embryo proper. This patterning requires a signaling cascade involving the BMP, WNT and NODAL pathways; however, how these pathways regulate one another in space and time to generate cell-fate patterns remains unknown. Using a human gastruloid model, we show that BMP signaling initiates a wave of WNT signaling, which, in turn, initiates a wave of NODAL signaling. While WNT propagation depends on continuous BMP activity, NODAL propagates independently of upstream signals. We further show that the duration of BMP signaling determines the position of mesodermal differentiation while WNT and NODAL synergize to achieve maximal differentiation. The waves of both WNT and NODAL signaling activity extend farther into the colony than mesodermal differentiation. Combining dynamic measurements of signaling activity with mathematical modeling revealed that the formation of signaling waves is inconsistent with WNT and NODAL forming a stable spatial pattern in signaling activities, and the final signaling state is spatially homogeneous. Thus, dynamic events in the BMP, WNT, and NODAL signaling cascade, in the absence of a signaling gradient, have the potential to mediate epiblast patterning.

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Section: Introductionmentioning

confidence: 99%

Dissecting the dynamics of signaling events in the BMP, WNT, and NODAL cascade during self-organized fate patterning in human gastruloids

Chhabra

Liu

Goh

et al. 2018

Preprint

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“…The BMP, WNT and NODAL signaling cascade is important during mammalian gastrulation and gastruloid formation in micropattern (Chhabra et al, 2018;Martyn et al, 2018). Specifically, WNT and NODAL pathways synergize to instruct mesoderm differentiation in gastruloids, whereas changes in the duration of BMP signaling alter the position of mesodermal ring (Chhabra et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

High-resolution transcriptional and morphogenetic profiling of cells from micropatterned human embryonic stem cell gastruloid cultures

Fu²,

He³

et al. 2020

Preprint

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During mammalian gastrulation, germ layers arise and are shaped into the body plan while extraembryonic layers sustain the embryo. Human embryonic stem cells, cultured with BMP4 on extracellular matrix micro-discs, reproducibly differentiate into gastruloids, expressing markers of germ layers and extraembryonic cells with radial organization. Single-cell RNA sequencing and cross-species comparisons with mouse and cynomolgus monkey gastrulae suggest that gastruloids contain seven major cell types, including epiblast, ectoderm, mesoderm, endoderm, and extraembryonic trophoblast-and amnion-like cells. Upon gastruloid dissociation, single cells reseeded onto micro-discs were motile and aggregated with the same but segregated from distinct cell types. Ectodermal cells segregated from endodermal and extraembryonic cells but mixed with mesodermal cells. Our work demonstrates that the gastruloid system supports primate-specific features of embryogenesis, and that gastruloid cells exhibit evolutionarily conserved sorting behaviors. This work generates a resource for transcriptomes of human extraembryonic and embryonic germ layers differentiated in a stereotyped arrangement.

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“…In embryonic development, many growth factor pathways including fibroblast growth factor (FGF), bone morphogenetic protein, Wnt, retinoic acid, Hedgehog, Nodal, and Notch [15][16][17] are fundamental for the establishment of the three germ layers. Specifically, Wnt/β-catenin pathway activation is known to play major roles in endodermal and mesodermal pattering and formation during embryonic development and have been accordingly studied in different model organisms [15,[18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Adenomatous Polyposis Coli as a Major Regulator of Human Embryonic Stem Cells Self-Renewal

2019

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Human embryonic stem cells (hESCs) provide an essential tool to investigate early human development, study disease pathogenesis, and examine therapeutic interventions. Adenomatous polyposis coli (APC) is a negative regulator of Wnt/β‐catenin signaling, implicated in the majority of sporadic colorectal cancers and in the autosomal dominant inherited syndrome familial adenomatous polyposis (FAP). Studies into the role of Wnt/β‐catenin signaling in hESCs arrived at conflicting results, due at least in part to variations in culture conditions and the use of external inhibitors and agonists. Here, we directly targeted APC in hESCs carrying a germline APC mutation, derived from affected blastocysts following preimplantation genetic diagnosis (PGD) for FAP, in order to answer open questions regarding the role of APC in regulating pluripotency and differentiation potential of hESCs. Using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9), we generated second hit APC mutations in FAP‐hESCs. Despite high CRISPR/Cas9 targeting efficiency and the successful isolation of many clones, none of the isolated clones carried a loss of function mutation in the wild‐type (WT) APC allele. Using a fluorescent β‐catenin reporter and analysis of mutated‐allele frequencies in the APC locus, we show that APC double mutant hESCs robustly activate Wnt/β‐catenin signaling that results in rapid differentiation to endodermal and mesodermal lineages. Here, we provide direct evidence for a strict requirement for constant β‐catenin degradation through the APC destruction complex in order to maintain pluripotency, highlighting a fundamental role for APC in self‐renewal of hESCs. Stem Cells 2019;37:1505–1515

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Self-organization of a human organizer by combined Wnt and Nodal signalling

Cited by 245 publications

References 21 publications

Dissecting the dynamics of signaling events in the BMP, WNT, and NODAL cascade during self-organized fate patterning in human gastruloids

Dissecting the dynamics of signaling events in the BMP, WNT, and NODAL cascade during self-organized fate patterning in human gastruloids

High-resolution transcriptional and morphogenetic profiling of cells from micropatterned human embryonic stem cell gastruloid cultures

Adenomatous Polyposis Coli as a Major Regulator of Human Embryonic Stem Cells Self-Renewal

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