MCC regulator of WNT signaling pathway (MCC) is a podocyte essential gene
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ABSTRACT:
PROVIDER: PRJNA774350 | ENA |
REPOSITORIES: ENA
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Project description:Podocytes are an integral part of the glomerular infiltration barrier. At present, many genes are known essential for podocyte survival and structural and functional homeostasis; however, there are more such genes to be uncovered. By single-cell RNA-seq of mouse podocytes, we detected the expression of gene encoding MCC regulator of WNT signaling pathway (MCC) in majority of the single podocytes and speculated that MCC may be essential for podocytes. We confirmed MCC expression in mouse podocytes and further showed its expression in human podocytes. To experimentally prove the essentiality of MCC for podocytes, we knocked down MCC in cultured podocytes, resulting in marked morphological change of cell shape, cytoskeletal stress fiber disruption, increased apoptosis, and downregulation of podocyte essential genes, CD2AP and WT1, demonstrating that MCC is essential for podocytes. To investigate the mechanism underlying the role of MCC in podocytes, we performed RNA-seq analysis of the podocytes in culture 24 hours after transfection of siRNA against MCC, followed by bioinformatics analysis of the genes with altered expression, and found some mechanistic clues. Lastly, we found that MCC is downregulated in podocytes treated with puromycin aminonucleosides and in glomeruli of diabetic mice and FSGS patients, implicating MCC in the development of podocytopathy and proteinuria. In conclusion, MCC is essential for podocytes and its deficiency may be involved in podocytopathy.
2021-12-23 | GSE186547 | GEO
Project description:Podocytes are an integral part of the glomerular filtration barrier. Many genes are already known to be essential for podocyte survival, structure and function, but there are more podocyte essential genes to be identified. By single-cell RNA-seq of mouse podocytes, we detected the expression of gene encoding MCC regulator of WNT signaling pathway (MCC) in majority of the podocytes and speculated that MCC is essential for podocytes. We confirmed MCC expression in mouse podocytes and further showed its expression in human podocytes. To experimentally prove the essentiality of MCC for podocytes, we knocked down MCC in cultured podocytes and found marked morphological change of cell shape, cytoskeletal F-actin stress fiber disruption, increased apoptosis, and downregulation of podocyte essential genes, CD2AP and WT1, demonstrating that MCC is essential for podocytes. Since MCC has been implicated in cell cycle and β-catenin signaling, we examined the expression of cell cycle related genes and activity of β-catenin in the MCC knockdown podocytes, but did not find significant changes. To further explore the mechanism underlying the role of MCC in podocytes, we performed RNA-sequencing and bioinformatics analysis of MCC knockdown podocytes and found a significant enrichment of the regulated genes in lamellipodia formation. Consistently, we found that MCC is present in lamellipodia and MCC knockdown resulted in loss of lamellipodia in the cells. Lastly, we found that MCC was downregulated in podocytes treated with puromycin aminonucleosides and in glomeruli of diabetic mice and FSGS patients, implicating MCC is involved in the development of podocytopathy and proteinuria. In conclusion, MCC is potentially essential for podocytes and its downregulation may be involved in podocytopathy.
| S-EPMC8674659 | biostudies-literature
Project description:When using cell lines to study cancer, phenotypic similarity to the original tumor is paramount. Yet, little has been done to characterize how closely Merkel cell carcinoma (MCC) cell lines model native tumors. To determine their similarity to MCC tumor samples, we characterized MCC cell lines via gene expression microarrays. Using whole transcriptome gene expression signatures and a computational bioinformatic approach, we identified significant differences between variant cell lines (UISO, MCC13, and MCC26) and fresh frozen MCC tumors. Conversely, the classic WaGa and Mkl-1 cell lines more closely represented the global transcriptome of MCC tumors. When compared to publicly available cancer lines, WaGa and Mkl-1 cells were similar to other neuroendocrine tumors, but the variant cell lines were not. WaGa and Mkl-1 cells grown as xenografts in mice had histological and immunophenotypical features consistent with MCC, while UISO xenograft tumors were atypical for MCC. Spectral karyotyping and short tandem repeat analysis of the UISO cells matched the original cell line's description, ruling out contamination. Our results validate the use of transcriptome analysis to assess the cancer cell line representativeness and indicate that UISO, MCC13, and MCC26 cell lines are not representative of MCC tumors, whereas WaGa and Mkl-1 more closely model MCC. RNA was extracted from MCC cell lines and MCC and SCLC tumor samples and hybridized to Affymetrix microarrays for transcriptome profiling.
2014-12-23 | E-GEOD-50451 | biostudies-arrayexpress
Project description:Podocytes are essential cells of the renal blood filter. They structurally compose the renal blood filter by interdigitating with neighboring podocytes by the means of a modified adherens junction, the slit membrane. In podocyte injury, loss of podocytes is a common feature. Podocyte loss could be mediated by the cleavage of podocyte cell adhesion molecules through the A Disintegrin and Metalloproteinase 10 (ADAM10). Here we show that ADAM10 is highly abundant at the site of blood filtration, namely at podocyte foot processes. Podocyte-expressed ADAM10 is not required for the development of the renal filter but plays a major role in podocyte injury. Following antibody-mediated injury, ADAM10 is upregulated in humans and mice. ADAM10 activity results in the cleavage of cell-cell adhesion molecules. This cleavage paves the way for an activation of the injury related Wnt/-catenin signaling pathway and for podocyte loss. We therefore conclude that ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury. As part of this project, we have analyzed the membrane proteome of murin podocytes to evaluate the abundance of membrane bound proteases.
2021-02-19 | PXD022213 | Pride
Project description:The rapid regeneration of the small intestinal epithelium is sustained by crypt intestinal stem cells (ISCs). Wnt/b-catenin signaling is essential for intestinal crypt homeostasis and maintenance of Lgr5+ ISC, and yet no single or combinatorial knockout of Frizzled (FZD) genes, representing Wnt receptors, has phenocopied the severe intestinal epithelial effects of Wnt signaling blockade. The elusive identification of specific Frizzled (Fzd) receptor(s) underlying homeostatic proliferation and ISC function would greatly inform therapeutic mucosal repair strategies. In prior pharmacologic studies, bioengineered antagonists that block Wnt binding to both FZD5 and FZD8 receptors induced lethal crypt and villus loss, implicating FZD5 and/or FZD8 as essential for ISCs maintenance. Here, the potential function of Fzd5 in during intestinal homeostasis was examined by epithelial-specific Fzd5 ko, which rapidly elicited lethal pan-intestinal crypt and villus loss, and by Lgr5-specific Fzd5 cKO, which strongly reduced Lgr5+ ISC while inducing their premature differentiation. In parallel, Fzd5 cKO potently repressed Wnt target gene expression, with phenotypic rescue by constitutive activation of b-catenin in vivo and confirmation upon in vitro organoid culture. Fzd5 cKO but not Fzd8 cKO in organoids ablated responsiveness to dual specificity bioengineered FZD5/FZD8-selective Wnt surrogate agonists, which reversed DSS-induced colitis phenotypes in both wild-type and Fzd8 cKO mice. Overall, our results implicate the FZD5 receptor as an essential regulator of crypt homeostasis, Lgr5+ ISCs and intestinal response to bioengineered Wnt surrogate agonists.
2024-10-18 | GSE233260 | GEO
Project description:FZD5 is an essential regulator of intestinal crypt homeostasis and surrogate Wnt agonist response
| PRJNA975582 | ENA
Project description:Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1-CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for proliferation and maintaining cell identity in MCC. There is growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.
2020-09-04 | GSE147816 | GEO
Project description:Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1-CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for proliferation and maintaining cell identity in MCC. There is growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.
2020-09-04 | GSE147815 | GEO
Project description:Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1-CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for proliferation and maintaining cell identity in MCC. There is growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.
2020-09-04 | GSE148103 | GEO
Project description:Microarray analysis of the molecular phenotype of the glomerular podocyte during temperature shift-induced differentiation Keywords = glomerular podocyte Keywords = differentiation
2010-05-26 | E-GEOD-1545 | biostudies-arrayexpress