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Bighead is a Wnt antagonist secreted by the Xenopus Spemann organizer that promotes Lrp6 endocytosis

ABSTRACT: Bighead is a Wnt antagonist secreted by the Xenopus Spemann organizer that promotes Lrp6 endocytosis

PROVIDER: PRJNA416291 | ENA |

REPOSITORIES: ENA

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			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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Bighead is a Wnt antagonist secreted by the Xenopus Spemann organizer that promotes Lrp6 endocytosis

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

Pharmaceutical reversal of Dkk1-induced LRP6 endocytosis prevents cancer cachexia and prolongs survival

Project description:Cancer cachexia with profound weight loss and frailty impairs quality of life, limits cancer therapy and decreases survival, against which no effective therapy is available. Dkk1 is a secreted antagonist of Wnt/β-catenin pathway via interacting with Wnt co-receptors LRP5 and 6 (LRP5/6) and inducing their endocytosis1-4. Although Dkk1 is critical for animal development3,5, its mRNA is undetectable in most adult organs6. Of note, elevated circulating Dkk1 leads to poor prognosis in patients with a variety of types of cancer by a completely unknown mechanism. Here, we show that administration of a recombinant Dkk1 protein accelerated cancer cachexia-related death through inducing LRP6 endocytosis but not β-catenin inhibition, whereas pharmacological blockade of Dkk1-induced membrane LRP6 downregulation completely prevented cancer cachexia and robustly prolonged survival in tumor-bearing mice. Pharmacological blockade of Dkk1-induced membrane LRP6 downregulation prevented alterations of a number of GPCR pathways and all main cancer cachexia-related pathways in skeletal muscle of mice bearing tumor as shown by a genome-wide transcriptional analysis. Furthermore, Dkk1 injection into hindlimb directly triggered activations of GPCR pathways and cachexia-related pathways. These findings establish a key role of the Dkk1-LRP6 axis in cancer cachexia development through affecting GPCR pathways and suggest a highly promising therapeutic approach for preventing cancer cachexia.

2024-12-01 | GSE121873 | GEO

Bighead is a Wnt antagonist secreted by the <i>Xenopus</i> Spemann organizer that promotes Lrp6 endocytosis.

| S-EPMC6166843 | biostudies-literature

Pharmaceutical reversal of Dkk1-induced LRP6 endocytosis prevents cancer cachexia and prolongs survival

Project description:Pharmaceutical reversal of Dkk1-induced LRP6 endocytosis prevents cancer cachexia and prolongs survival

| PRJNA498701 | ENA

Transcriptional profiling of small intestinal crypts from mice treated with Notch blocking antibodies or Notch blocking antibodies in combination with an Lrp6 blocking antibody.

2015-03-11 | GSE66751 | GEO

Transcriptional profiling of small intestinal crypts from mice treated with Notch blocking antibodies or Notch blocking antibodies in combination with an Lrp6 blocking antibody.

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.

2015-03-11 | E-GEOD-66751 | biostudies-arrayexpress

Embyoid organizer

Project description:Embyoid organizer

| PRJNA1021143 | ENA

Transcriptome analysis of LRP5- and LRP6-depleted HCC38 cells.

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.

2018-06-06 | GSE109004 | GEO

Sequencing facilitates quantitative analysis of transcriptomes in wild type and Lrp6-knockdown cells

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.

2018-08-20 | GSE102770 | GEO

Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann organizer.

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.

| S-EPMC3061830 | biostudies-literature

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