Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptional response to endothelial cell-specific inactivation of Tspan12 in the mature retina

ABSTRACT: Blood-retina barrier (BRB) formation and retinal angiogenesis depend on beta-catenin signaling induced by the ligand norrin (NDP), the receptor frizzled4 (FZD4), co-receptor LRP5, and the tetraspanin TSPAN12. Impaired NDP/FZD4 signaling causes familial exudative vitreoretinopathy (FEVR), which may lead to blindness. Endothelial-cell specific inactivation of the Tspan12 gene at P28 using a Cdh5-CreERT2 driver shows that TSPAN12 functions in ECs to promote vascular morphogenesis and BRB formation in developing mice, and BRB maintenance in adult mice. 12 month after Tspan12 inactivation and loss of BRB maintenance with massive IgG and albumin extravasation we observe complement activation, cystoid edema, and impaired beta-wave in electroretinograms. RNA-Seq 6 month after Tspan12 inactivation provides a detailed view on the transcriptional response, including activation of antibody effector systems (complement and Fc receptors), inflammation and microglia responses, extracellular matrix organization and remodeling, and other responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE113878 | GEO | 2018/10/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Therapeutic modulation of the blood-brain barrier and ischemic stroke by a bioengineered FZD4-selective WNT surrogate

Project description:Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's disease. The Norrin/FZD4/TSPAN12 pathway activates WNT/-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD4-selective ligand Norrin. Here, we developed L6-F4-2, a non-lipidated, FZD4-specific surrogate with significantly improved sub-picomolar affinity versus native Norrin. In Norrin knockout (NdpKO) mice, L6-F4-2 not only potently reversed neonatal retinal angiogenesis deficits, but also restored BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduced BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD4-selective WNT surrogate during ischemic BBB dysfunction, with general applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.

2023-01-31 | GSE223498 | GEO

Therapeutic modulation of the blood-brain barrier and ischemic stroke by a bioengineered FZD4-selective WNT surrogate (bulk)

2023-01-31 | GSE223628 | GEO

Project description:Whole exome sequencing revealed fifteen variants in NDP, FZD4, LRP5 and TSPAN12 genes for thirteen families with familial exudative vitreoretinopathy

| PRJNA752456 | ENA

Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits b-catenin degedation

Project description:Ablation of tetraspanin protein TSPAN12 from human MDA-MB-231 cells resulted in a major decrease in primary tumor xenograft growth, accompanied by a significant increase in tumor apoptosis. Furthermore, TSPAN12 removal markedly increased metastasis to mouse lungs, due to enhanced tumor-endothelial interactions. Removal of TSPAN12 from human MDA-MB-231 cells also caused substantial proteosomal degradation of Î²-catenin, a key effecter of canonical Wnt signalling. This may be explained by TSPAN12 ablation leading to diminished association between FZD4 (a key receptor in the canonical Wnt pathway) and its co-receptor LRP5. Consistent with disruption of canonical Wnt signaling, TSPAN12 ablation altered the expression of LRP5, Naked 1 and 2, DVL2, DVL3, Axin 1 and GSKÎ²3 proteins, and also altered expression of several genes regulated by Î²-catenin. In conclusion, these results provide the first evidence for TSPAN12 playing a role in supporting primary tumor growth and suppressing metastasis. TSPAN12 appears to function by stabilizing FZD4-LRP5 association, in support of canonical Wnt-pathway signaling, leading to enhanced Î²-catenin expression and function. 4 samples = 2 Control + 2 TSPAN12KD

2012-10-29 | E-GEOD-41892 | biostudies-arrayexpress

Gene expression profile at single cell level of P26 WT, Tspan12 KO, F4L5.13 treated Tspan12 KO mice retina

Project description:We used single cell RNA sequencing (scRNA-seq) to discover the gene expression changes in Tspan12 KO retina, and evaluated the effect of F4L5.13 (Frizzled4:LRP5 agonist) treatment on transcriptional normalization in Tspan12 KO retina.

2023-05-22 | GSE213887 | GEO

Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits β-catenin degradation

Project description:Ablation of tetraspanin protein TSPAN12 from human MDA-MB-231 cells significantly decreased primary tumor xenograft growth, while increasing tumor apoptosis. Furthermore, TSPAN12 removal markedly enhanced tumor-endothelial interactions and increased metastasis to mouse lungs. TSPAN12 removal from human MDA-MB-231 cells also caused diminished association between FZD4 (a key canonical Wnt pathway receptor) and its co-receptor LRP5. The result likely explains substantially enhanced proteosomal degradation of β-catenin, a key effecter of canonical Wnt signalling. Consistent with disrupted canonical Wnt signaling, TSPAN12 ablation altered expression of LRP5, Naked 1 and 2, DVL2, DVL3, Axin 1 and GSKβ3 proteins. TSPAN12 ablation also altered expression of several genes regulated by β-catenin (e.g. CCNA1, CCNE2, WISP1, ID4, SFN, ME1) that may help to explain altered tumor growth and metastasis. In conclusion, these results provide the first evidence for TSPAN12 playing a role in supporting primary tumor growth and suppressing metastasis. TSPAN12 appears to function by stabilizing FZD4-LRP5 association, in support of canonical Wnt-pathway signaling, leading to enhanced β-catenin expression and function.

2012-10-29 | GSE41892 | GEO

RNA-seq analysis of NDP and F4L5.13 treated bEnd.3 endothelial cell line

Project description:bEnd.3 cells were treated with NDP (Norrin) or F4L5.13 (FZD4-LRP5 agonist) for 8 or 24 hours

2021-05-03 | GSE166764 | GEO

Norrin-dependent gene expression in cerebellar granule neuron progenitors

Project description:Medulloblastoma (MB), a tumor of the cerebellum, is the most common malignant brain tumor in children. One third of all human MB exhibits a gene expression signature of Sonic hedgehog (Shh) signaling. Hedgehog (Hh) pathway inhibitors have shown efficacy in clinical trials for MB, however, tumors develop resistance to these compounds, highlighting the need to identify additional therapeutic targets for treatment. We have identified a role for Norrin signaling in tumor initiation in the Patched (Ptch) mouse model of MB. Norrin is a secreted factor that functions as an atypical Wnt by binding to the Frizzled4 (Fzd4) receptor on endothelial cells to activate canonical beta-catenin-mediated Wnt signaling pathway. In the cerebellum, activation of Norrin/Fzd4 signaling is required for the establishment and maintenance of the blood brain barrier (BBB). We have identified a role for Norrin signaling in the stroma as a potent tumor inhibitory signal. Inactivation of Norrin in Ptch+/- mice significantly shortens latency and increases MB incidence. This phenotype is associated with an increased frequency of pre-tumor lesions and their conversion to malignancy. In this context, loss of Norrin signalling in endothelial cells is associated with an accelerated transition to a pro-tumor stroma characterized by vascular permeability, inflammation and angiogenic remodelling. Accordingly, loss of Ndp significantly alters the stromal gene expression signature of established Ptch MB.

2016-10-12 | GSE81962 | GEO

Norrin-dependent gene expression in Patched mouse medulloblastoma

2016-10-12 | GSE81963 | GEO

Gene expression profile at single cell levels of post natal day 7 mouse cerebellar subdural meningeal cells

Project description:The microenvironment exerts a profound control on tumor initiation in many tissues. In brain tumors, this process is under studied, in particular how stromal signals exert effects on cancer signaling in pre-tumor cells. In the cerebellum, canonical Wnt signalling mediated by Norrin/Frizzled4 (Fzd4) activation in endothelial cells in the meninges exerts a potent inhibitory effect on preneoplasia and tumour progression in mouse models of Sonic hedgehog medulloblastoma (Shh-MB). Single cell transcriptome profiling and deep phenotyping of the meninges during the critical period of preneoplasia development revealed that Norrin/Fzd4 signalling maintains the activation of meningeal macrophages (mMΦs), characterized by Lyve1 and CXCL4 expression. mMΦ depletion during this critical period phenocopies the enhanced preneoplasia and tumourigenesis caused by Ndp loss. CXCL4 mediates the anti-tumourigenesis effect of mMΦs, as it antagonizes CXCL12/CXCR4 signaling in granule neuron progenitors, the MB cell of origin, to reduce cell cycle progression and promote migration away from the pre-tumour niche. Taken together, these findings are the first demonstration that mMΦs are key mediators of chemokine-regulated anti-cancer cross talk between the stroma and pre-tumour cells in the control of MB initiation.

2023-08-28 | GSE226805 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data