Dusp1 modulates activin/smad2 mediated germ layer specification via FGF signal inhibition in Xenopus embryos

Goutam

Umair

et al. 2021

Cells

Self Cite

Inhibition of the bone morphogenetic proteins (BMPs) is the primary step toward neuroectoderm formation in vertebrates. In this process, the Spemann organizer of the dorsal mesoderm plays a decisive role by secreting several extracellular BMP inhibitors such as Chordin (Chrd). Chrd physically interacts with BMP proteins and inhibits BMP signaling, which triggers the expression of neural-specific transcription factors (TFs), including Foxd4l1.1. Thus, Chrd induces in a BMP-inhibited manner and promotes neuroectoderm formation. However, the regulatory feedback mechanism of Foxd4l1.1 on mesodermal genes expression during germ-layer specification has not been fully elucidated. In this study, we investigated the regulatory mechanism of Foxd4l1.1 on chrd (a mesodermal gene). We demonstrate that Foxd4l1.1 inhibits chrd expression during neuroectoderm formation in two ways: First, Foxd4l1.1 directly binds to FRE (Foxd4l1.1 response elements) within the chrd promoter region to inhibit transcription. Second, Foxd4l1.1 physically interacts with Smad2 and Smad3, and this interaction blocks Smad2 and Smad3 binding to activin response elements (AREs) within the chrd promoter. Site-directed mutagenesis of FRE within the chrd(-2250) promoter completely abolished repressor activity of the Foxd4l1.1. RT-PCR and reporter gene assay results indicate that Foxd4l1.1 strongly inhibits mesoderm- and ectoderm-specific marker genes to maintain neural fate. Altogether, these results suggest that Foxd4l1.1 negatively regulates chrd transcription by dual mechanism. Thus, our study demonstrates the existence of precise reciprocal regulation of chrd transcription during neuroectoderm and mesoderm germ-layer specification in Xenopus embryos.

Section: Luciferase Assaysmentioning

confidence: 99%

Foxd4l1.1 Negatively Regulates Chordin Transcription in Neuroectoderm of Xenopus Gastrula

Goutam

Umair

et al. 2021

Cells

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“…Activin-mediated mesoderm induction critically depends on FGF signaling, as demonstrated when DNFR led to complete loss of mesodermal genes expression due to activin [111]. In comparison, ectopic expression of Smad2 significantly elevates expression of various FGFs and FGFRs including fgf3, fgf8, fgf20, fgfr1, and fgfr2 [92]. Supporting the role of FGFR signaling in mesoderm induction is also observed with the expression profile of several FGF ligands in early mesoderm of vertebrate embryos.…”

Section: Fgf In Mesoderm Inductionmentioning

confidence: 63%

“…FGF signaling then showed an inhibitory effect on endodermal differentiation and blocking FGF signaling with DNFR in ectodermal explants induced en-dodermal specific genes endodermin (edd) and mixer expression [91]. Recently, Dusp1 (dual specificity phosphatase 1, a FGF signaling modulator) reported to increase the expression of edd, mixer, and sox17β (endodermal marker) in a activin/smad2-dependent manner [92]. The one possible explanation of this observation may be additional expression of dusp1 with smad2 might inhibit the FGF signaling and indirectly induces smad2 mediated endodermal differentiation.…”

Section: Role Of Fgf Signaling In Endoderm Formationmentioning

confidence: 99%

“…An ectopic gain of function of sef, for example, has been shown to reduce phosphorylation of Raf1 and MEK1/2 [199]. Other agents that have been reported are Spred [200], Pyst1/Mkp3 [197], Dusp1 [92], and FRS2α/β [201], all endogenous FGF inhibitors/modulators. All of the above mentioned blockers of FGF signaling may have separate or overlapping targets (see Table 2) and are generally cytosolic effector proteins.…”

Section: Endogenous Protein Inhibitorsmentioning

confidence: 99%

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Functional Roles of FGF Signaling in Early Development of Vertebrate Embryos

Goutam

Park

et al. 2021

Cells

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Fibroblast growth factors (FGFs) comprise a large family of growth factors, regulating diverse biological processes including cell proliferation, migration, and differentiation. Each FGF binds to a set of FGF receptors to initiate certain intracellular signaling molecules. Accumulated evidence suggests that in early development and adult state of vertebrates, FGFs also play exclusive and context dependent roles. Although FGFs have been the focus of research for therapeutic approaches in cancer, cardiovascular disease, and metabolic syndrome, in this review, we mainly focused on their role in germ layer specification and axis patterning during early vertebrate embryogenesis. We discussed the functional roles of FGFs and their interacting partners as part of the gene regulatory network for germ layer specification, dorsal–ventral (DV), and anterior-posterior (AP) patterning. Finally, we briefly reviewed the regulatory molecules and pharmacological agents discovered that may allow modulation of FGF signaling in research.

“…Activin signaling regulates other signaling pathways for mesoderm development in Xenopus . For example, activin reportedly induces the expression of fgf3/ 8, and also induces the negative regulator of FGF signaling, dusp1 , for the dorsoventral patterning of mesoderm 40 . Furthermore, activin signaling reportedly activates the expression of downstream genes of p53 signaling, p21waf1 and pal-1, and the mesendoderm gene, mix.2 , through the cooperative action with p53 41 – 43 .…”

Section: Discussionmentioning

confidence: 99%

Temporal transcriptomic profiling reveals dynamic changes in gene expression of Xenopus animal cap upon activin treatment

Satou-Kobayashi

Fukamizu

et al. 2021

Sci Rep

Activin, a member of the transforming growth factor-β (TGF-β) superfamily of proteins, induces various tissues from the amphibian presumptive ectoderm, called animal cap explants (ACs) in vitro. However, it remains unclear how and to what extent the resulting cells recapitulate in vivo development. To comprehensively understand whether the molecular dynamics during activin-induced ACs differentiation reflect the normal development, we performed time-course transcriptome profiling of Xenopus ACs treated with 50 ng/mL of activin A, which predominantly induced dorsal mesoderm. The number of differentially expressed genes (DEGs) in response to activin A increased over time, and totally 9857 upregulated and 6663 downregulated DEGs were detected. 1861 common upregulated DEGs among all Post_activin samples included several Spemann’s organizer genes. In addition, the temporal transcriptomes were clearly classified into four distinct groups in correspondence with specific features, reflecting stepwise differentiation into mesoderm derivatives, and a decline in the regulation of nuclear envelop and golgi. From the set of early responsive genes, we also identified the suppressor of cytokine signaling 3 (socs3) as a novel activin A-inducible gene. Our transcriptome data provide a framework to elucidate the transcriptional dynamics of activin-driven AC differentiation, reflecting the molecular characteristics of early normal embryogenesis.