Reich S and Weinstein DC (2019), Repression of Inappropriate Gene Expression in ...

XB-ART-56463

Genes (Basel) 2019 Nov 06;1011:. doi: 10.3390/genes10110895.

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Repression of Inappropriate Gene Expression in the Vertebrate Embryonic Ectoderm.

Reich S , Weinstein DC .

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During vertebrate embryogenesis, precise regulation of gene expression is crucial for proper cell fate determination. Much of what we know about vertebrate development has been gleaned from experiments performed on embryos of the amphibian Xenopus laevis; this review will focus primarily on studies of this model organism. An early critical step during vertebrate development is the formation of the three primary germ layers-ectoderm, mesoderm, and endoderm-which emerge during the process of gastrulation. While much attention has been focused on the induction of mesoderm and endoderm, it has become clear that differentiation of the ectoderm involves more than the simple absence of inductive cues; rather, it additionally requires the inhibition of mesendoderm-promoting genes. This review aims to summarize our current understanding of the various inhibitors of inappropriate gene expression in the presumptive ectoderm.

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Species referenced: Xenopus laevis
Genes referenced: ascl1 bambi chrd cripto.3 dand5 foxh1.2 foxi1 gmnn gsc hdac1 ndp nodal smad2 smad3 smad4 smad7 smurf2 srf tbx2 tbxt tmeff1 tp53 trim33 vegt wnt8a znf585b
GO keywords: gastrulation

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	Figure 1. Diagram of Xenopus laevis embryo during early gastrulation. During gastrulation, the three primary germ layers, endoderm, mesoderm, and ectoderm, begin to differentiate. The vegetal pole refers to the lower hemisphere of the embryo and will give rise to the endoderm. The marginal zone refers to the equatorial region of the embryo between the animal and vegetal poles and will give rise to the mesoderm. The mesoderm contains a dorsal organizer region which secretes Bone Morphogenetic Protein (BMP) antagonists. The animal pole refers to the upper hemisphere of the embryo which will give rise to the ectoderm. The drawing of the cavity in the animal hemisphere depicts the fluid-filled blastocoel. As described in the text of the review, foxI1e, along with many other germ layer-enriched factors, is expressed in the cells of the animal pole. chordin and goosecoid are expressed in the dorsal marginal zone. wnt8 is expressed ventrolaterally and brachyury is expressed throughout the marginal zone. VegT, an activator of nodal and nodal-like genes, is expressed in the cells of the vegetal pole.
	Figure 2. Extracellular regulation of mesendodermal gene expression. In this and subsequent figures, red boxes denote mesendoderm inhibitors. R-Smads refer to Smads1/5/8 or Smads2/3 for the BMP and Activin/Nodal pathways, respectively. TGFÎ² ligands (BMP4 and Activin/Nodal) bind the TGFÎ² receptor complex and activate signal transduction of the TGFÎ² signaling pathway. Dand5 (Coco) and Ndp (Norrin) physically associate with BMP and Activin/Nodal and inhibit signal transduction.
	Figure 3. Transmembrane and cytosolic inhibition of mesendodermal gene expression. TMEFF1, a transmembrane protein, prevents the association between Cripto, a Nodal-pathway specific coreceptor, and the type I receptor. Smad7 inhibits TGFÎ² signaling by forming a complex with Smurf2, which subsequently induces the degradation of the type I and type II TGFÎ² receptors. BAMBI, another transmembrane protein, associates with Smad7 and the type I receptor and inhibits association between the type I receptor and R-Smads. The â€œXâ€ indicates the lack of a serine/threonine intracellular kinase domain.
	Figure 4. Nuclear regulation of mesendodermal gene silencing. Trim33 (Ectodermin) functions in the nucleus and, via ubiquitination, promotes the degradation of Smad4. At the transcriptional level, SRF prevents the association between FoxH1 and the Smad2-Smad4 complex, repressing Smad2 target genes. Eaf1/2 are repressors that inhibit Activin-mediated mesoderm induction via P53-dependent and P53-independent mechanisms. Eaf1/2 physically associates with P53, Smad2, Smad3, and FoxH1. ZNF585B (XFDL156) reduces the amount of P53 bound to P53 target sites and represses P53-induced mesodermal gene expression. FoxI1e is an activator that likely indirectly inhibits mesendodermal gene expression in the ectoderm. Tbx2, a T-box transcription factor, also represses mesendodermal gene expression. Geminin is a chromatin modifier that represses gene expression by recruiting the PRC2 complex. The PRC2 complex then trimethylates H3K27 to silence gene expression. Ascl1, another chromatin modifier, recruits HDAC1 to deacetylate H3K27 and H3K9, a mechanism that silences gene expression.

References [+] :

Amaya, FGF signalling in the early specification of mesoderm in Xenopus. 1993, Pubmed, Xenbase