Formation of definitive endoderm

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R-HSA-9823730
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Homo sapiens
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The endoderm in mammalian embryos originates from two different populations of cells: the visceral endoderm, which is present before gastrulation as the hypoblast underlying the epiblast, and the definitive endoderm, which is derived from epiblast cells ingressing through the anterior-most region of the primitive streak. After ingression, the cells of the definitive endoderm then intercalate with the cells of the visceral endoderm to form the embryonic endoderm that will give rise to the gut and visceral organs associated with the gut such as the pancreas and liver (reviewed in Lewis and Tam 2006, Nowotschin et al. 2019). In the discoid human gastrula (differs from the rodent gastrula which acquires a cup shape), the endoderm initially is organized in a flat epithelial sheet that later rolls into a tube to form the gut. Due to ethical considerations, research on gastrulation is undertaken primarily in non-human primate species (for example Bergmann et al. 2022) and stem cells (D'Amour et al. 2005, reviewed in Salehin et al. 2022), which have provided insight into germ layer formation in human embryos.
The definitive endoderm originates in the anterior region of the primitive streak where there are high levels of NODAL signaling (inferred from mouse embryos in Vincent et al. 2003) and lower levels of BMP signaling (inferred from mouse embryos in Bachiller et al. 2000) and Wnt signaling (inferred from mouse embryos in Mukhopadhyay et al. 2001). In mouse, Eomesodermin (EOMES), whose expression is activated by NODAL signaling via SMAD2 and SMAD3 in the primitive streak, is required for formation of both mesoderm and endoderm (Arnold et al. 2008). Experiments in human embryonic stem cells and mouse embryos indicate that EOMES is a core element of a gene regulatory network that specifies definitive endoderm by activating expression of transcription factors such as FOXA2 and SOX17 which then activate sets of endodermally expressed genes (Teo et al. 2011, Chia et al. 2019). As endoderm progenitors enter the primitive streak they redistribute E-cadherin (CDH1) on their surface, which may play a role in sorting the cells into an epithelial layer (inferred from mouse homologs in Viotti et al. 2014). Unlike mesoderm, endoderm progenitors do not undergo a complete epithelial to mesenchymal transition (EMT) (inferred from mouse embryos and stem cells in Scheibner et al. 2021). They do not switch cadherin expression from E-cadherin (CDH1) to N-cadherin (CDH2) and do not require the EMT transcription factor SNAI1 (in ferred from mouse homologs in Scheibner et al. 2021). The endodermal transcription factor FOXA2 may repress EMT activity (in ferred from the mouse homolog in Scheibner et al. 2021).
Though no single marker gene is expressed exclusively in definitive endoderm, the definitive endoderm is characterized by the expression of a combination of genes, including FOXA2, SOX17, GATA4, GATA6, CXCR4, GSC, and E-cadherin (CDH1). CDH1, a general marker of epithelial cells, and the chemokine receptor CXCR4 are often used together as surface markers of definitive endoderm (inferred from mouse homologs in Yasunaga et al. 2005).
Literature References
PubMed ID Title Journal Year
11702953 Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse

Westphal, H, Rodriguez-Esteban, C, Izpisúa Belmonte, JC, Shtrom, S, Niehrs, C, Tsukui, T, Dorward, DW, Gomer, L, Glinka, A, Grinberg, A, Chen, L, Huang, SP, Mukhopadhyay, M

Dev Cell 2001
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
36398790 Mammalian gastrulation: signalling activity and transcriptional regulation of cell lineage differentiation and germ layer formation

Knowles, H, Masamsetti, VP, Tam, PPL, Salehin, N

Biochem Soc Trans 2022
12842913 Cell fate decisions within the mouse organizer are governed by graded Nodal signals

Dunn, NR, Hayashi, S, Norris, DP, Vincent, SD, Robertson, EJ

Genes Dev 2003
10688202 The organizer factors Chordin and Noggin are required for mouse forebrain development

May, SR, Belo, JA, Rossant, J, Klingensmith, J, De Robertis, EM, Harland, RM, Anderson, RM, Kemp, C, Bachiller, D, McMahon, JA, McMahon, AP

Nature 2000
18171685 Pivotal roles for eomesodermin during axis formation, epithelium-to-mesenchyme transition and endoderm specification in the mouse

Bikoff, EK, Hofmann, UK, Arnold, SJ, Robertson, EJ

Development 2008
16258519 Efficient differentiation of human embryonic stem cells to definitive endoderm

Eliazer, S, Kelly, OG, D'Amour, KA, Baetge, EE, Agulnick, AD, Kroon, E

Nat Biotechnol 2005
35709828 Spatial profiling of early primate gastrulation in utero

Hollfelder, F, Slatery, E, Drummer, C, Reik, W, Bergmann, S, Behr, R, Siriwardena, D, Boroviak, TE, Kohler, TN, Sasaki, E, Tewary, M, Vickers, A, Clark, S, Strawbridge, SE, Kishimoto, K, Penfold, CA

Nature 2022
31160415 The endoderm: a divergent cell lineage with many commonalities

Nowotschin, S, Hadjantonakis, AK, Campbell, K

Development 2019
16311587 Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells

Torikai-Nishikawa, S, Nishikawa, S, Jakt, LM, Tada, S, Yasunaga, M, Era, T, Nakano, Y, Nishikawa, S, Okada, M, Chiba, T

Nat Biotechnol 2005
25419850 SOX17 links gut endoderm morphogenesis and germ layer segregation

Nowotschin, S, Hadjantonakis, AK, Viotti, M

Nat Cell Biol 2014
16752393 Definitive endoderm of the mouse embryo: formation, cell fates, and morphogenetic function

Lewis, SL, Tam, PPL

Dev Dyn 2006
21663792 Pluripotency factors in embryonic stem cells regulate differentiation into germ layers

Zou, LN, Liu, SJ, Thomson, M, Ramanathan, S, Meissner, A, Smith, Z

Cell 2011
30629940 GATA6 Cooperates with EOMES/SMAD2/3 to Deploy the Gene Regulatory Network Governing Human Definitive Endoderm and Pancreas Formation

Dunn, NR, Garcia-Bernardo, J, Chia, CY, Hattersley, AT, Madrigal, P, Vallier, L, Chhatriwala, M, Denil, SLIJ, El-Khairi, R, Shepherd, MH, Martinez, I

Stem Cell Reports 2019
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