Dissecting the dynamics of signaling events in the BMP, WNT, and NODAL cascade during self-organized fate patterning in human gastruloids
| Autor: | Lizhong Liu, Aryeh Warmflash, Xiangyu Kong, Ryan Goh, Sapna Chhabra |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Embryology Cellular differentiation Human Embryonic Stem Cells Nodal signaling Bone Morphogenetic Protein 4 Mesoderm 0302 clinical medicine Signal Initiation Cell Signaling Biology (General) WNT Signaling Cascade General Neuroscience Mechanisms of Signal Transduction Wnt signaling pathway Cell Differentiation Signaling Cascades Cell biology Organoids medicine.anatomical_structure embryonic structures General Agricultural and Biological Sciences Research Article Signal Transduction BMP signaling Signal Inhibition animal structures Nodal Protein QH301-705.5 SMAD signaling Biology Models Biological General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Paracrine signalling medicine Humans Benzothiazoles Body Patterning Models Statistical General Immunology and Microbiology Embryos Gastrulation Biology and Life Sciences Cell Biology Gastrula Wnt Proteins 030104 developmental biology Gene Expression Regulation Epiblast NODAL 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Biology, Vol 17, Iss 10, p e3000498 (2019) PLoS Biology |
| ISSN: | 1545-7885 1544-9173 |
| Popis: | During 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. A self-organizing in vitro model of cell fate decisions during human gastrulation reveals that patterning is controlled by combinatorial dynamics of multiple signaling pathways, rather than by stable gradients. |
| Databáze: | OpenAIRE |
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