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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE66751 | GEO | 2015/03/11

SECONDARY ACCESSION(S): PRJNA277860

REPOSITORIES: GEO

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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

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

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

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

| PRJNA416291 | ENA

Generation of anti-Notch antibodies and their application in blocking Notch signalling in neural stem cells.

Project description:Notch signalling occurs via direct cell-cell interactions and plays an important role in linking the fates of neighbouring cells. There are four different mammalian Notch receptors that can be activated by five cell surface ligands. The ability to inhibit specific Notch receptors would help identify the roles of individual family members and potentially provide a means to study and control cell differentiation. Anti-Notch antibodies in the form of single chain Fvs were generated from an antibody phage display library by selection on either the ligand binding domain or the negative regulatory region (NRR) of Notch1 and Notch2. Six antibodies targeting the NRR of Notch1 and four antibodies recognising the NRR of Notch2 were found to prevent receptor activation in cell-based luciferase reporter assays. These antibodies were potent, highly specific inhibitors of individual Notch receptors and interfered with endogenous signalling in stem cell systems of both human and mouse origin. Antibody-mediated inhibition of Notch efficiently down-regulated transcription of the immediate Notch target gene hairy and enhancer of split 5 (Hes5) in both mouse and human neural stem cells and revealed a redundant regulation of Hes5 in these cells as complete down-regulation was seen only after simultaneous blocking of Notch1 and Notch2. In addition, these antibodies promoted differentiation of neural stem cells towards a neuronal fate. In contrast to the widely used small molecule ?-secretase inhibitors, which block all 4 Notch receptors (and a multitude of other signalling pathways), antibodies allow blockade of individual Notch family members in a highly specific way. Specific inhibition will allow examination of the effect of individual Notch receptors in complex differentiation schemes regulated by the co-ordinated action of multiple signalling pathways.

| S-EPMC3502869 | biostudies-literature

LRP5 and LRP6 are required for maintaining self-renewal and differentiation of hematopoietic stem cells

Project description:The canonical Wnt signaling pathway has been demonstrated as a critical role in the self-renewal, proliferation and differentiation of Hematopoietic Stem Cells (HSCs), but the functions are indeterminacy in adult HSCs since the different experimental systems using gain- or loss- functions mice models. Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6) are important co-receptors in the canonical Wnt/β-catenin pathway. In this study, the knockout mice models were established for adult HSC investagation via conditional ablation of LRP5 and LRP6 in adult hematopoiesis by Vav-Cre Loxp system. We found the HSC numbers were diminished due to the decreased proliferation and cell cycle. To investigate the molecular mechanisms, RNA-seq was performed using HSC cells isolated from WT and dKO mice.

2018-12-31 | GSE122635 | GEO

Mapk7 regulates bone-fat balance by targeting Lrp6/β-catenin axis

Project description:The lineage commitment and differentiation of mesenchymal stem cells (MSCs) play a crucial role in the maintenance of bone stability. MAPK7 (Mitogen-activated protein kinase 7), a member of the MAPK family, controls cell proliferation, differentiation, and survival. However, the specific role of Mapk7 in regulating the osteogenic and adipogenic differentiation of MSCs remains to be determined. In this study, depletion of Mapk7 in MSCs (Prx1-Cre) resulted in severe low bone mass and accumulation of bone marrow fat in mice exhibiting osteoporosis. In vitro, overexpression of Mapk7 in MSCs induced an enhancement of osteogenesis in MSCs, while adipogenesis was attenuated. Mechanistically, MAPK7 availed to influence the activity of WNT/β-catenin signaling by modulating the phosphorylation of LRP6 ser1490, which ultimately impacted the osteogenic-adipogenic differentiation fate of MSCs for the first time. This is of great clinical and scientific significance for understanding the biological function of Mapk7 gene and developing new therapeutic targets for OP. Our study for the first time demonstrates that Mapk7/Lrp6/β-catenin signal axis plays a critical role in regulating the osteogenic and adipogenic differentiation of MSCs. It also suggests that modulating the function of Mapk7 may benefit the treatment of MSCs differentiation inbalance related bone diseases such as osteoporosis.

2024-02-15 | GSE255596 | GEO

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

Project description:Transcriptome analysis of LRP5- and LRP6-depleted HCC38 cells.

| PRJNA429432 | ENA

Merlin inhibits Wnt/?-catenin signaling by blocking LRP6 phosphorylation.

Project description:Merlin, encoded by the NF2 gene, is a tumor suppressor that acts by inhibiting mitogenic signaling and is mutated in Neurofibromatosis type II (NF2) disease, although its molecular mechanism is not fully understood. Here, we observed that Merlin inhibited Wnt/?-catenin signaling by blocking phosphorylation of LRP6, which is necessary for Wnt signal transduction, whereas mutated Merlin in NF2 patients did not. Treatment with Wnt3a enhanced phosphorylation of Ser518 in Merlin via activation of PAK1 in a PIP2-dependent manner. Phosphorylated Merlin dissociated from LRP6, allowing for phosphorylation of LRP6. Tissues from NF2 patients exhibited higher levels of ?-catenin, and proliferation of RT4-D6P2T rat schwannoma cells was significantly reduced by treatment with chemical inhibitors of Wnt/?-catenin signaling. Taken together, our findings suggest that sustained activation of Wnt/?-catenin signaling due to abrogation of Merlin-mediated inhibition of LRP6 phosphorylation may be a cause of NF2 disease.

| S-EPMC5041192 | biostudies-literature

Combination of two novel blocking antibodies, anti-PD-1 antibody ezabenlimab (BI 754091) and anti-LAG-3 antibody BI 754111, leads to increased immune cell responses.

Project description:Upregulation of inhibitory receptors, such as lymphocyte activation gene-3 (LAG-3), may limit the antitumor activity of therapeutic antibodies targeting the programmed cell death protein-1 (PD-1) pathway. We describe the binding properties of ezabenlimab, an anti-human PD-1 antibody, and BI 754111, an anti-human LAG-3 antibody, and assess their activity alone and in combination. Ezabenlimab bound with high affinity to human PD-1 (KD = 6 nM) and blocked the interaction of PD-1 with PD-L1 and PD-L2. Ezabenlimab dose-dependently increased interferon-γ secretion in human T cells expressing PD-1 in co-culture with PD-L1-expressing dendritic cells. Administration of ezabenlimab to human PD-1 knock-in mice dose-dependently inhibited growth of MC38 tumors. To reduce immunogenicity, ezabenlimab was reformatted from a human IgG4 to a chimeric variant with a mouse IgG1 backbone (BI 905725) for further in vivo studies. Combining BI 905725 with anti-mouse LAG-3 antibodies improved antitumor activity versus BI 905725 monotherapy in the MC38 tumor model. We generated BI 754111, which bound with high affinity to human LAG-3 and prevented LAG-3 interaction with its ligand, major histocompatibility complex class II. In an in vitro model of antigen-experienced memory T cells expressing PD-1 and LAG-3, interferon-γ secretion increased by an average 1.8-fold versus isotype control (p = 0.027) with BI 754111 monotherapy, 6.9-fold (p < 0.0001) with ezabenlimab monotherapy and 13.2-fold (p < 0.0001) with BI 754111 plus ezabenlimab. Overall, ezabenlimab and BI 754111 bound to their respective targets with high affinity and prevented ligand binding. Combining ezabenlimab with BI 754111 enhanced in vitro activity versus monotherapy, supporting clinical investigation of this combination (NCT03156114; NCT03433898).

| S-EPMC9225207 | biostudies-literature

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