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Primitive streak formation

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-9754189

PubChem

R-HSA-9754189

Description

Due to ethical considerations, most research on mammalian gastrulation has been performed on mouse embryos. Therefore most of the reactions described in this section are the results of research in mouse embryos. Significant research has also been performed on non-human primates such as cynomolgus monkeys (Macaca fascicularis) (Nakamura et al. 2016, Sasaki et al. 2016). More recently, human gastrula-like cell assemblages ("gastruloids") generated from pluripotent stem cells have been developed (Moris et al. 2020) and are now being compared with mouse embryos (reviewed in Rossant and Tam 2021, Ghimire et al. 2021).
At the beginning of gastrulation in the mouse, the primitive streak forms in a region of BMP, WNT, FGF, and NODAL signaling. In the mouse embryo, NODAL is expressed throughout the epiblast before anterior-posterior axis induction and is required for pluripotency (reviewed in Robertson 2014). NODAL signaling is restricted to the posterior side of the embryo by the secretion of NODAL and WNT antagonists (CER1, LEFTY1) from the anterior visceral endoderm (AVE) (reviewed in Stower and Srinivas 2014). In human embryonic stem cells (hESCs) NODAL is also crucial for maintenance of pluripotency (James et al. 2005, Vallier et al. 2004). In mouse embryos, NODAL and WNT3 are required for formation of the primitive streak (Conlon et al. 1994, Brennan et al. 2001, Liu et al. 1999) and NODAL expression subsequently becomes restricted to the node at the anterior end of the primitive streak (Zhou et al. 1993). Pro-NODAL secreted by the epiblast in response to BMP4 signalling from the extraembryonic ectoderm is converted to mature NODAL by furin (PCSK3) secreted from the extraembryonic ectoderm. NODAL maintains BMP4 expression in the extraembryonic ectoderm which then activates WNT3 in the posterior epiblast. WNT signaling, in turn, amplifies NODAL expression (Brennan et al. 2001). The order of events in this signaling cascade may be different in human embryos due to differences in early embryo architecture.
NODAL, BMP, and WNT show similar effects on human 2D gastruloids (Martyn et al. 2019). Mesoderm and definitive endoderm progenitors appear to be already separate and distinct in the primitive streak, therefore bipotential mesendoderm progenitors may be transitory if they exist (Probst et al. 2021). This is an area of ongoing research.
Mesoderm is formed by an epithelial-mesenchymal transition that produces an ingression of cells through the primitive streak. Endoderm does not show a complete epithelial-mesenchymal transition and instead forms by cell plasticity (a partial epithelial-mesenchymal transition in which both E-cadherin and N-Cadherin are expressed) (inferred from mouse embryos in Scheibner et al. 2021). However, in mouse embryos endoderm progenitors still ingress through the anterior region of the primitive streak, migrate with mesoderm cells, and eventually integrate into the visceral endoderm layer to give rise to the definitive endoderm (Viotti et al. 2014).
Specific types of mesoderm are formed sequentially according to the time and position of ingression of cells through the primitive streak. This patterning is caused by gradients of NODAL, WNT, and BMP signaling that activate transcriptional programs in the mesoderm progenitors.
T-box transcription factor T (TBXT, T, Brachyury) and Eomesodermin (EOMES) are two of the first transcription factors expressed in mesoderm and endoderm progenitors in the primitive streak (reviewed in Probst and Arnold 2016). The two factors combined are required for formation of all mesoderm and endoderm (Arnold et al. 2008, Tosic et al. 2019).
TBXT is activated by WNT signaling (via beta-catenin acting with LEF1 or TCF1) and BMP4 and is expressed in mesodermal and axial mesodermal progenitors and in the primitive streak during gastrulation, later becoming localized to the notochord and tailbud. TBXT is an early marker of mesodermal differentiation and is often used in studies of embryonic stem cells. In hESCs TBXT is expressed in both mesodermal and endodermal progenitors, it regulates different sets of target genes depending on the signaling environment (Faial et al. 2015).
Expression of EOMES is activated by NODAL via SMAD2 and SMAD3 and is observed in the posterior epiblast prior to formation of the primitive streak and in mesoderm and endoderm progenitors during the first day of gastrulation. EOMES in combination with SMAD2,3 is crucial for the activation of definitive endoderm genes (Teo et al. 2011). TBXT and EOMES generally activate expression of mesoderm genes and repress expression of genes associated with pluripotency such as SOX2 and NANOG.
Some transcription factors are particularly important for regulating gastrulation and are also used as markers for particular stages and morphological features. For example, Goosecoid (GSC) expression marks the onset of gastrulation, is first observed in the primitive streak, and becomes localized to the anterior end of the primitive streak and then the axial mesoderm (Blum et al. 1992). SMAD2 and SMAD3 activated by NODAL are recruited to the GSC promoter by FOXH1, which is already located at the promoter. MIXL1 also binds the GSC promoter and activates expression. In mice, GSC is a regulator of head development.
MIXL1 is required for formation of both mesoderm and definitive endoderm (Hart et al. 2002) and is expressed early throughout the primitive streak and in nascent mesoderm cells exiting the streak. Expression of MIXL1 is mediated downstream by NODAL through SMAD2 and SMAD3 binding to the promoter of MIXL1. EOMES also plays a direct role in activating MIXL1 and GSC expression in hESCs (Teo et al. 2011) and in mouse embryos (Tosic et al. 2019)..
Developing mesoderm becomes specified by expression of transcription factors such as MESP1, a marker of cardiac progenitors. (See the Reactome pathway "Cardiogenesis".)

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying **all 10** entries
UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
O15178	T-box transcription factor T	T TBXT	view
O75593	Forkhead box protein H1	FAST1 FAST2 FOXH1	view
O95936	Eomesodermin homolog	EOMES TBR2	view
P12644	Bone morphogenetic protein 4	BMP2B BMP4 DVR4	view
P35222	Catenin beta-1	CTNNB CTNNB1 OK/SW-cl.35 PRO2286	view
P48431	Transcription factor SOX-2	SOX2	view
Q01860	POU domain, class 5, transcription factor 1	OCT3 OCT4 OTF3 POU5F1	view
Q13485	SMAD family member 4	DPC4 MADH4 SMAD4	view
Q9UJU2	Lymphoid enhancer-binding factor 1	LEF1	view
Q9UPN9	E3 ubiquitin-protein ligase TRIM33	KIAA1113 RFG7 TIF1G TRIM33	view

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