scholarly journals Local cell interactions and self-amplifying individual cell ingression drive amniote gastrulation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Octavian Voiculescu ◽  
Lawrence Bodenstein ◽  
I-Jun Lau ◽  
Claudio D Stern
Keyword(s):  
Large Scale ◽  
Epithelial To Mesenchymal Transition ◽  
Primitive Streak ◽  
Cell Interactions ◽  
Mesenchymal Transition ◽  
Deep Layers ◽  
Single Sheet ◽  
Epithelial Sheet ◽  
Local Cell ◽  
Cell Intercalation

Gastrulation generates three layers of cells (ectoderm, mesoderm, endoderm) from a single sheet, while large scale cell movements occur across the entire embryo. In amniote (reptiles, birds, mammals) embryos, the deep layers arise by epithelial-to-mesenchymal transition (EMT) at a morphologically stable midline structure, the primitive streak (PS). We know very little about how these events are controlled or how the PS is maintained despite its continuously changing cellular composition. Using the chick, we show that isolated EMT events and ingression of individual cells start well before gastrulation. A Nodal-dependent ‘community effect’ then concentrates and amplifies EMT by positive feedback to form the PS as a zone of massive cell ingression. Computer simulations show that a combination of local cell interactions (EMT and cell intercalation) is sufficient to explain PS formation and the associated complex movements globally across a large epithelial sheet, without the need to invoke long-range signalling.

scholarly journals Molecular mechanism of symmetry breaking in a 3D model of a human epiblast

2018 ◽  
Author(s):  
Mijo Simunovic ◽  
Jakob J. Metzger ◽  
Fred Etoc ◽  
Anna Yoney ◽  
Albert Ruzo ◽  
...  
Keyword(s):  
Symmetry Breaking ◽  
Axial Symmetry ◽  
3D Model ◽  
Epithelial To Mesenchymal Transition ◽  
Embryonic Stem ◽  
Primitive Streak ◽  
Molecular Evidence ◽  
Axis Formation ◽  
Mesenchymal Transition

ABSTRACTBreaking the anterior-posterior (AP) symmetry in mammals takes place at gastrulation. Much of the signaling network underlying this process has been elucidated in the mouse, however there is no direct molecular evidence of events driving axis formation in humans. Here, we use human embryonic stem cells to generate an in vitro 3D model of a human epiblast whose size, cell polarity, and gene expression are similar to a 10-day human epiblast. A defined dose of bone mor-phogenetic protein 4 (BMP4) spontaneously breaks axial symmetry, and induces markers of the primitive streak and epithelial to mesenchymal transition. By gene knockouts and live-cell imaging we show that, downstream of BMP4, WNT3 and its inhibitor DKK1 play key roles in this process. Our work demonstrates that a model human epiblast can break axial symmetry despite no asymmetry in the initial signal and in the absence of extraembryonic tissues or maternal cues. Our 3D model opens routes to capturing molecular events underlying axial symmetry breaking phenomena, which have largely been unexplored in model human systems.

scholarly journals BMP4-induced symmetry breaking in a 3D model of the human epiblast

2019 ◽  
Author(s):  
Mijo Simunovic ◽  
Ali H. Brivanlou ◽  
Eric D. Siggia
Keyword(s):  
Live Cell Imaging ◽  
3D Model ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Imaging ◽  
Embryonic Stem ◽  
Primitive Streak ◽  
Mesenchymal Transition ◽  
Pluripotency Markers ◽  
Anterior Posterior

Abstract We describe the protocol of generating a 3D stem-cell-based model of the human pre-gastrulation epiblast by culturing human embryonic stem cells in a mix of hydrogel and Matrigel. Much like the epiblast of an in vitro attached day-10 human embryo, this model is an epithelial sphere with a cavity at its center, it is expressing key pluripotency markers, and it displays apico-basal polarity. The 3D colonies can further be differentiated with morphogens and in the case of intermediate concentrations of BMP4, they break the anterior-posterior symmetry characterized by an asymmetric expression of a primitive streak marker and showing signs of epithelial to mesenchymal transition. The protocol described here is suitable for immunofluorescence staining and for live-cell imaging.

scholarly journals Mouse primitive streak forms in situ by initiation of epithelial to mesenchymal transition without migration of a cell population

2011 ◽  
Vol 241 (2) ◽  
pp. 270-283 ◽  
Author(s):  
Margot Williams ◽  
Carol Burdsal ◽  
Ammasi Periasamy ◽  
Mark Lewandoski ◽  
Ann Sutherland
Keyword(s):  
Cell Population ◽  
Epithelial To Mesenchymal Transition ◽  
Primitive Streak ◽  
Mesenchymal Transition ◽  
A Cell

A Novel Biomimetic Model for Studying Mechanics of Embryonic Morphogenesis and Differentiation

2010 ◽  
Author(s):  
Julia A. Henkels ◽  
Evan A. Zamir
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Primitive Streak ◽  
Mitotic Cell ◽  
Embryonic Cells ◽  
Mesenchymal Transition ◽  
Genetics Research ◽  
Undifferentiated Cells ◽  
Organizing Center ◽  
Important Time ◽  
Anterior Posterior

Before the explosion of genetics research in the last century, embryonic development was largely studied from a mechanical perspective. Paired with genetic advances in understanding developmental signaling pathways and induction mechanisms, an important goal for understanding morphogenesis is to discover how the genome codes for changes in the mechanical movements of the embryonic cells. After formation of the zygote, a phase of rapid mitotic cell division is followed by epithelialization resulting in a cohesive sheet of cells termed the epiblast. During the next major phase of triploblastic development called gastrulation, a group of undifferentiated cells in the epiblast moves collectively to the embryonic midline and eventually gives rise to the three primary germ layers: endoderm, mesoderm, and ectoderm. At the primitive streak—the “organizing center” in amniotes (reptiles, birds, and mammals) which delineates anterior-posterior polarity—prospective endodermal and mesodermal precursors undergo epithelial-to-mesenchymal transition (EMT), internalization, and eventually organogenesis. “It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life” (Lewis Wolpert, 1986).

scholarly journals Self-organization of a functional human organizer by combined WNT and NODAL signalling

2017 ◽  
Author(s):  
I. Martyn ◽  
T.Y. Kanno ◽  
A. Ruzo ◽  
E.D. Siggia ◽  
A.H. Brivanlou
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Embryonic Stem ◽  
Primitive Streak ◽  
Model Organisms ◽  
Detailed Characterization ◽  
Mesenchymal Transition ◽  
Neural Fate ◽  
Secondary Axis ◽  
Human Embryology ◽  
Emt Markers

In amniotes, the development of the primitive streak (PS) and its accompanying “organizer” define the first stages of gastrulation. Despite detailed characterization in model organisms, the analogous human structures remain a mystery. We have previously shown that when stimulated with BMP4, micropatterned colonies of human embryonic stem cells (hESCs) self-organize to generate early embryonic germ layers1. Here we show that in the same type of colonies WNT signalling is sufficient to induce a PS, and WNT with ACTIVIN is sufficient to induce an organizer, as characterized by embryo-like sharp boundary formation, epithelial-to-mesenchymal transition (EMT) markers, and expression of the organizer specific transcription factor GSC. Moreover, when grafted into chick embryos, WNT and ACTIVIN treated human cells induce and contribute autonomously to a secondary axis while inducing neural fate in the host. This fulfills the most stringent functional criteria for an organizer, and its discovery represents a major milestone in human embryology.

scholarly journals Cell intercalation driven by SMAD3 underlies secondary neural tube formation

2020 ◽  
Author(s):  
Elena Gonzalez-Gobartt ◽  
José Blanco-Ameijeiras ◽  
Susana Usieto ◽  
Guillaume Allio ◽  
Bertrand Benazeraf ◽  
...  
Keyword(s):  
Neural Tube ◽  
Epithelial To Mesenchymal Transition ◽  
De Novo ◽  
Tube Formation ◽  
List Type ◽  
Lumen Formation ◽  
Mesenchymal Transition ◽  
Cell Intercalation ◽  
Neural Tube Formation

SUMMARYBody axis elongation is a hallmark of the vertebrate embryo, involving the architectural remodelling of the tailbud. Although it is clear how bi-potential neuro-mesodermal progenitors (NMPs) contribute to embryo elongation, the dynamic events that lead to de novo lumen formation and that culminate in the formation of a 3-Dimensional, secondary neural tube from NMPs, are poorly understood. Here, we used in vivo imaging of the chicken embryo to show that cell intercalation downstream of TGF-beta/SMAD3 signalling is required for secondary neural tube formation. Our analysis describes the initial events in embryo elongation including lineage restriction, the epithelial-to-mesenchymal transition of NMPs, and the initiation of lumen formation. Importantly, we show that the resolution of a single, centrally positioned continuous lumen, which occurs through the intercalation of central cells, requires SMAD3 activity. We anticipate that these findings will be relevant to understand caudal, skin-covered neural tube defects, amongst the most frequent birth defects detected in humans.HIGHLIGHTS.- Initiation of the lumen formation follows the acquisition of neural identity and epithelial polarization..- Programmed cell death is not required for lumen resolution..- Resolution of a single central lumen requires cell intercalation, driven by Smad3 activity.- The outcome of central cell division preceding cell intercalation, varies along the cranio-caudal axis.

Conditional activation of RhoA suppresses the epithelial to mesenchymal transition at the primitive streak during mouse gastrulation

2004 ◽  
Vol 318 (3) ◽  
pp. 665-672 ◽  
Author(s):  
Toshimitsu Fuse ◽  
Yoshiakira Kanai ◽  
Masami Kanai-Azuma ◽  
Misao Suzuki ◽  
Kazuhiro Nakamura ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Primitive Streak ◽  
Mesenchymal Transition

scholarly journals SMARCA4 Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5474
Author(s):  
Jihyun Kim ◽  
Gyubeom Jang ◽  
Sung Hoon Sim ◽  
In Hae Park ◽  
Kyungtae Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Large Scale ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Triple Negative ◽  
Cisplatin Resistance ◽  
Gene Activation ◽  
Atpase Subunit ◽  
Mesenchymal Transition

The role of SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, in genomic organization is well studied in various cancer types. However, its oncogenic role and therapeutic implications are relatively unknown in triple-negative breast cancer (TNBC). We investigated the clinical implication and downstream regulation induced by SMARCA4 inactivation using large-scale genome and transcriptome profiles. Additionally, SMARCA4 was knocked out in MDA-MB-468 and MDA-MB-231 using CRISPR/Cas9 to identify gene regulation and a targetable pathway. First, we observed an increase in SMARCA4 mutations in cisplatin resistance and metastasis in TNBC patients. Its inactivation was associated with the mesenchymal-like (MSL) subtype. Gene expression analysis showed that the epithelial-to-mesenchymal transition (EMT) pathway was activated in SMARCA4-deficient patients. Next, the Hippo pathway was activated in the SMARCA4 inactivation group, as evidenced by the higher CTNNB1, TGF-β, and YAP1 oncogene signature scores. In SMARCA4 knockout cells, EMT was upregulated, and the cell line transcriptome changed from the SL to the MSL subtype. SMARCA4 knockout cells showed cisplatin resistance and Hippo-YAP/TAZ target gene activation. The YAP1 inhibitor verteporfin suppressed the expression of YAP1 target genes, and decreased cell viability and invasiveness on SMARCA4 knockout cells. SMARCA4 inactivation in TNBC endowed the resistance to cisplatin via EMT activation. The YAP1 inhibitor could become a novel strategy for patients with SMARCA4-inactivated TNBC.

scholarly journals Abl suppresses cell extrusion and intercalation during epithelium folding

2016 ◽  
Vol 27 (18) ◽  
pp. 2822-2832 ◽  
Author(s):  
Jeanne N. Jodoin ◽  
Adam C. Martin
Keyword(s):  
Cell Shape ◽  
Epithelial To Mesenchymal Transition ◽  
Adherens Junction ◽  
Apical Constriction ◽  
Mesenchymal Transition ◽  
Abl Tyrosine Kinase ◽  
Cell Intercalation ◽  
Shape Changes ◽  
Insight Into ◽  
Cell Extrusion

Tissue morphogenesis requires control over cell shape changes and rearrangements. In the Drosophila mesoderm, linked epithelial cells apically constrict, without cell extrusion or intercalation, to fold the epithelium into a tube that will then undergo epithelial-to-mesenchymal transition (EMT). Apical constriction drives tissue folding or cell extrusion in different contexts, but the mechanisms that dictate the specific outcomes are poorly understood. Using live imaging, we found that Abelson (Abl) tyrosine kinase depletion causes apically constricting cells to undergo aberrant basal cell extrusion and cell intercalation. abl depletion disrupted apical–basal polarity and adherens junction organization in mesoderm cells, suggesting that extruding cells undergo premature EMT. The polarity loss was associated with abnormal basolateral contractile actomyosin and Enabled (Ena) accumulation. Depletion of the Abl effector Enabled (Ena) in abl-depleted embryos suppressed the abl phenotype, consistent with cell extrusion resulting from misregulated ena. Our work provides new insight into how Abl loss and Ena misregulation promote cell extrusion and EMT.

scholarly journals Epithelial-to-Mesenchymal Transition and Neoangiogenesis in Laryngeal Squamous Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3339
Author(s):  
Leonardo Franz ◽  
Lorenzo Nicolè ◽  
Anna Chiara Frigo ◽  
Giancarlo Ottaviano ◽  
Piergiorgio Gaudioso ◽  
...  
Keyword(s):  
Large Scale ◽  
Epithelial To Mesenchymal Transition ◽  
Cox Regression ◽  
Epithelial Mesenchymal Transition ◽  
Cox Model ◽  
Disease Free Survival ◽  
Predictive Performance ◽  
Therapy Resistance ◽  
Prognostic Models ◽  
Mesenchymal Transition

The mechanism of epithelial–mesenchymal transition (EMT) is fundamental for carcinogenesis, tumor progression, cancer cell invasion, metastasis, recurrence, and therapy resistance, comprising important events, such as cellular junction degradation, downregulation of epithelial phenotype markers, overexpression of mesenchymal markers, and increase in cellular motility. The same factors that drive epithelial cells toward a mesenchymal phenotype may also drive endothelial cells toward a proangiogenic phenotype. The aim of this exploratory study was to investigate a potential interplay between EMT and angiogenesis (quantified through CD105 expression) in laryngeal carcinoma (LSCC). CD105-assessed microvessel density (MVD) and EMT markers (E-cadherin, N-cadherin, Snail, Slug, Zeb1, and Zeb2) were assessed on 37 consecutive LSCC cases. The univariate Cox regression model identified pN+ status (p = 0.0343) and Slug expression (p = 0.0268) as predictive of disease-free survival (DFS). A trend toward significance emerged for CD105-assessed MVD (p = 0.0869) and N-cadherin expression (p = 0.0911). In the multivariate Cox model, pN-status, Slug, and N-cadherin expressions retained their significant values in predicting DFS (p = 0.0346, p = 0.0430, and p = 0.0214, respectively). Our data support the hypothesis of a mutual concurrence of EMT and angiogenesis in driving LSCC cells toward an aggressive phenotype. To better characterize the predictive performance of prognostic models based on EMT and angiogenesis, further large-scale prospective studies are required.

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