Epithelial-Mesenchymal Transition (EMT) during gastrulation

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Homo sapiens
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During the epithelial-mesenchymal transition (EMT) during gastrulation, epithelial cells in the primitive streak transition to dissociated mesenchymal cells, allowing them to leave the epithelial epiblast (reviewed in Francou and Anderson 2020). EMT is induced by FGF, WNT, NODAL, and BMP signaling pathways that are present on the posterior side of the embryo (reviewed in Morgani and Hadjantonakis 2021). The FGF pathway in particular has been implicated in the regulation of EMT during gastrulation (inferred from mouse embryos in Ciruna and Rossant 2001). In later stage cancer cells the TGFbeta signaling pathway is a major inducer of EMT that leads to metastasis (reviewed in Hao et al. 2019). During gastrulation BMP4 and NODAL of the TGFbeta pathways are also probably involved in EMT (Martyn et al. 2018).
This epithelial-mesenchymal transition (EMT) is responsible for formation of mesoderm. An incomplete EMT appears to be responsible for formation of endoderm (inferred from mouse embryos in Viotti et al. 2014, Scheibner et al. 2021). Prospective definitive endoderm cells leave the epiblast layer together with mesoderm cells and eventually integrate and displace the extraembryonic visceral endoderm layer (inferred from mouse embryos in Viotti et al. 2014).
SNAIL (SNAI1), a transcription factor activated in the primitive streak (inferred from the mouse homolog in Carver et al. 2001), participates in crucial events in the EMT that creates mesoderm: the downregulation of cell adhesion proteins E-cadherin (Cadherin-1, CDH1), Occludin (OLCN), and Claudins that results in loss of contact between cells. Instead, cells switch to expression of N-cadherin and mesenchymal gene programs.
Both EOMES and TBXT activate expression of SNAI1 at the primitive streak but not in definitive endoderm progenitors. SNAI1 represses CDH1 expression (reviewed in Bardot et al. 2020), OCLN expression (inferred from mouse homologs in Ikenouchi et al. 2003), and expression of Claudins (inferred from mouse homologs in Ikenouchi et al. 2003). Downregulation of CDH1 also occurs posttranslationally through an incompletely characterized mechanism involving NIK, p38 MAPK, and EBP41L5 (inferred from mouse homologs in Lee et al. 2007, Hirano et al. 2008). SNAI1 but not SNAI2 is required for proper EMT during gastrulation. Other factors required for EMT during gastrulation include p120-catenin, which regulates WNT signaling and EMT (inferred from mouse homologs in Hernandez-Martinez et al. 2019); Crumbs2, which promotes cell ingression (inferred from mouse homologs in Ramkumar et al. 2016); RhoA and microtubules, which control cell basement interactions (inferred from mouse homologs in Nakaya et al. 2008); and p38 and p38 interacting protein, which are critical for downregulating E-Cadherin (Zohn et al. 2006).

Literature References
PubMed ID Title Journal Year
32143751 Signaling regulation during gastrulation: Insights from mouse embryos and in vitro systems

Hadjantonakis, AK, Morgani, SM

Curr Top Dev Biol 2020
25349455 Gutsy moves in mice: cellular and molecular dynamics of endoderm morphogenesis

Hadjantonakis, AK, Viotti, M, Foley, AC

Philos Trans R Soc Lond B Biol Sci 2014
12668723 Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail

Tsukita, S, Furuse, M, Matsuda, M, Ikenouchi, J

J Cell Sci 2003
34168324 Epithelial cell plasticity drives endoderm formation during gastrulation

Böttcher, A, Ansarullah, A, Lickert, H, Cernilogar, FM, Beckers, J, Sterr, M, Burtscher, I, Büttner, M, Schotta, G, Scheibner, K, Theis, FJ, Schirge, S, Irmler, M, Yang, D

Nat Cell Biol 2021
32473204 Mouse gastrulation: Coordination of tissue patterning, specification and diversification of cell fate

Hadjantonakis, AK, Bardot, ES

Mech Dev 2020
29795348 Self-organization of a human organizer by combined Wnt and Nodal signalling

Siggia, ED, Martyn, I, Brivanlou, AH, Kanno, TY, Ruzo, A

Nature 2018
31195692 TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis

Baker, D, Ten Dijke, P, Hao, Y

Int J Mol Sci 2019
11689706 The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition

Carver, EA, Lan, Y, Gridley, T, Oram, KF, Jiang, R

Mol Cell Biol 2001
34113749 The Epithelial-to-Mesenchymal Transition (EMT) in Development and Cancer

Francou, A, Anderson, KV

Annu Rev Cancer Biol 2020
11703922 FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak

Rossant, J, Ciruna, B

Dev Cell 2001
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