Bighead is a Wnt antagonist secreted by the Xenopus Spemann organizer that promotes Lrp6 endocytosis
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ABSTRACT:
PROVIDER: PRJNA416291 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6234320.fastq.gz | Fastqsanger.gz | |||
| SRR6234330.fastq.gz | Fastqsanger.gz | |||
| SRR6234321.fastq.gz | Fastqsanger.gz | |||
| SRR6234322.fastq.gz | Fastqsanger.gz | |||
| SRR6234323.fastq.gz | Fastqsanger.gz |
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Project description:The Xenopus laevis embryo has been subjected to almost saturating screens for molecules specifically expressed in dorsal Spemann organizer tissue. In this study, we performed high-throughput RNA sequencing of ectodermal explants, called animal caps, which normally give rise to epidermis. We analyzed dissociated animal cap cells that, through sustained activation of MAPK, differentiate into neural tissue. We also microinjected mRNAs for Cerberus, Chordin, FGF8, BMP4, Wnt8, and Xnr2, which induce neural or other germ layer differentiations. The searchable database provided here represents a valuable resource for the early vertebrate cell differentiation. These analyses resulted in the identification of a gene present in frog and fish, which we call Bighead. Surprisingly, at gastrula, it was expressed in the Spemann organizer and endoderm, rather than in ectoderm as we expected. Despite the plethora of genes already mined from Spemann organizer tissue, Bighead encodes a secreted protein that proved to be a potent inhibitor of Wnt signaling in a number of embryological and cultured cell signaling assays. Overexpression of Bighead resulted in large head structures very similar to those of the well-known Wnt antagonists Dkk1 and Frzb-1. Knockdown of Bighead with specific antisense morpholinos resulted in embryos with reduced head structures, due to increased Wnt signaling. Bighead protein bound specifically to the Wnt coreceptor lipoprotein receptor-related protein 6 (Lrp6), leading to its removal from the cell surface. Bighead joins two other Wnt antagonists, Dkk1 and Angptl4, which function as Lrp6 endocytosis regulators. These results suggest that endocytosis plays a crucial role in Wnt signaling.
2017-12-01 | GSE106320 | GEO
Project description:The Xenopus laevis embryo has been subjected to almost saturating screens for molecules specifically expressed in dorsal Spemann organizer tissue. In this study, we performed high-throughput RNA sequencing of ectodermal explants, called animal caps, which normally give rise to epidermis. We analyzed dissociated animal cap cells that, through sustained activation of MAPK, differentiate into neural tissue. We also microinjected mRNAs for Cerberus, Chordin, FGF8, BMP4, Wnt8, and Xnr2, which induce neural or other germ layer differentiations. The searchable database provided here represents a valuable resource for the early vertebrate cell differentiation. These analyses resulted in the identification of a gene present in frog and fish, which we call Bighead. Surprisingly, at gastrula, it was expressed in the Spemann organizer and endoderm, rather than in ectoderm as we expected. Despite the plethora of genes already mined from Spemann organizer tissue, Bighead encodes a secreted protein that proved to be a potent inhibitor of Wnt signaling in a number of embryological and cultured cell signaling assays. Overexpression of Bighead resulted in large head structures very similar to those of the well-known Wnt antagonists Dkk1 and Frzb-1. Knockdown of Bighead with specific antisense morpholinos resulted in embryos with reduced head structures, due to increased Wnt signaling. Bighead protein bound specifically to the Wnt coreceptor lipoprotein receptor-related protein 6 (Lrp6), leading to its removal from the cell surface. Bighead joins two other Wnt antagonists, Dkk1 and Angptl4, which function as Lrp6 endocytosis regulators. These results suggest that endocytosis plays a crucial role in Wnt signaling.
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Project description:The goal of this study was to identify genes that are differentially expressed during a 24 hour Notch blockade and whether a Wnt antagonist (anti-Lrp6) could block this effect.
2015-03-11 | GSE66751 | GEO
Project description:The goal of this study was to identify genes that are differentially expressed during a 24 hour Notch blockade and whether a Wnt antagonist (anti-Lrp6) could block this effect. 3 condition experiment, Control untreated compared to N1N2 treated, and N1N2 treated compared to N1N2_Lrp6 treated. 5 biological replicates per condition.
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Project description:In order to characterize the differences between the co-receptors LRP5 and LRP6, we have analyzed the transcriptome of HCC38 cells - a triple negative breast cancer cell line - 24, 48 and 72 hours following the depletion of LRP5 or LRP6 using siRNAs.
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Project description:Purpose: The goals of this study are to determine the LRP6-mediated splicing regulation, and cellular transcriptomes from rat and human are analysised by deep sequencing. Methods: The mRNA profiles of WT and LRP6 KD were generated by deep sequencing, using Illumina HiSeq 4000. And the transcript isoform difference betwwen the two group were analysied by bioinformation, Semiquantitative PCR was performed to identify the analysis result. Results and conclusions: We detected a substantial number of Lrp6 loss-induced AS events, and up to nearly 50 of them were exon-skipped. A gene ontology analysis of the conserved LRP6-driven network showed enrichment for ninety-four genes encoding proteins mainly involved in cellular and metabolic processes . Among them, a decade of genes with LRP6-dependent isoform expression showed identical splicing patterns on the exon level across species. The RNA sequencing results were further verified by Semiquantitative PCR. We conclude that LRP6 could regulate mRNA splicing.
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Project description:Frzb-1 is a secreted protein containing a domain similar to the putative Wnt-binding region of the frizzled family of transmembrane receptors. Frzb-1 is widely expressed in adult mammalian tissues. In the Xenopus gastrula, it is expressed and regulated as a typical Spemann organizer component. Injection of frzb-1 mRNA blocks expression of XMyoD mRNA and leads to embryos with enlarged heads and shortened trunks. Frzb-1 antagonizes the effects of Xwnt-8 ectopic expression in a non-cell-autonomous manner. Cultured cells transfected with a membrane-tethered form of Wnt-1 bind epitope-tagged Frzb-1 in the 10(-10) M range. The results strengthen the view that the Spemann organizer is a source of secreted inhibitory factors.
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Project description:Studies of the Xenopus organizer have laid the foundation for our understanding of the conserved signaling pathways that pattern vertebrate embryos during gastrulation. Here, we use this wealth of knowledge as leverage in the design and analysis of a genomic visualization of organizer-related gene transcription. Using ectopic expression of the two major activities of the organizer, BMP and Wnt inhibition, as well as endogenous tissues, we generate a focused set of samples that represent different aspects of organizer signaling. The genomic expression values of each sample are then measured with oligonucleotide arrays. From this data, genes regulated by organizer signaling are selected and then clustered by their patterns of regulation. A new GO biological process annotation of the Xenopus genome allows us to rapidly identify clusters that are highly enriched for known gastrula patterning genes. Within these clusters, we can predict the expression patterns of unknown genes with remarkable accuracy, leading to the discovery of new organizer-related gastrula stage expression patterns for 19 genes. Moreover, the patterns of gene response observed within these clusters allow us to parse apart the contributions of BMP and Wnt inhibition in organizer function. We find that the majority of gastrula patterning genes respond transcriptionally to these activities according to only a few stereotyped patterns, allowing us to describe suites of genes that are likely to share similar regulatory mechanisms. These suites of genes demonstrate a mechanism where BMP inhibition initiates the organizer program before gastrulation, and Wnt inhibition maintains and drives the organizer program during gastrulation. Keywords: development, organizer, noggin, dkk-1, xenopus, gastrulation
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Project description:Activation of the Wnt pathway is at the core of many human cancers. During canonical Wnt signaling, the Lrp6 and Frizzled receptors bind to the Wnt growth factor, which leads to the complex being endocytosed. Glycogen Synthase Kinase 3 (GSK3), Dishevelled (Dvl), and Axin are sequestered inside the intraluminal vesicles of late endosomes, known as multivesicular bodies (MVBs). Here we present experiments showing that Wnt causes the endocytosis of focal adhesion (FA) proteins and depletion of Integrin β 1 (ITGβ1) from the cell surface. FAs and integrins provide link the cytoskeleton to the extracellular matrix. Wnt-induced macropinocytosis of the plasma membrane caused ITGβ1 depletion and was accompanied by striking changes in the actin cytoskeleton. In situ protease protection assays in cultured cells showed that ITGβ1 was sequestered within membrane-bounded organelles that corresponded to Wnt-induced MVBs containing GSK3 and focal adhesion-associated proteins. An in vivo model using Xenopus embryos dorsalized by Wnt8 mRNA showed that ITGβ1 depletion decreased Wnt signaling. The cross-talk between Wnt signaling, membrane trafficking, and focal adhesions should be relevant to human cancer and cell biology.
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