Innovative mouse models for the tumor suppressor activity of Protocadherin-10 isoforms
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ABSTRACT:
PROVIDER: PRJNA814256 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR18278806.fastq.gz | Fastqsanger.gz | |||
| SRR18278807.fastq.gz | Fastqsanger.gz | |||
| SRR18278808.fastq.gz | Fastqsanger.gz | |||
| SRR18278809.fastq.gz | Fastqsanger.gz | |||
| SRR18278810.fastq.gz | Fastqsanger.gz |
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Project description:Background: Nonclustered mouse protocadherin genes (Pcdh) encode proteins with a typical single ectodomain and a cytoplasmic domain with conserved motifs completely different from those of classic cadherins. Alternative splice isoforms differ in the size of these cytoplasmic domains. In view of the compelling evidence for gene silencing of protocadherins in human tumors, we started investigations on Pcdh functions in mouse cancer models. Methods: For Pcdh10, we generated two mouse lines: one with floxed exon 1, leading to complete Pcdh10 ablation upon Cre action, and one with floxed exons 2 and 3, leading to ablation of only the long isoforms of Pcdh10. In a mouse medulloblastoma model, we used GFAP-Cre action to locally ablate Pcdh10 in combination with Trp53 and Rb1 ablation. From auricular tumors, that also arose, we obtained tumor-derived cell lines, which were analyzed for malignancy in vitro and in vivo. By lentiviral transduction, we re-expressed Pcdh10 cDNAs. RNA-Seq analyses were performed on these cell families. Results: Surprisingly, not only medulloblastomas were generated in our model but also tumors of tagged auricles (pinnae). For both tumor types, ablation of either all or only long isoforms of Pcdh10 aggravated the disease. We argued that the perichondrial stem cell compartment is at the origin of the pinnal tumors. Immunohistochemical analysis of these tumors revealed different subtypes. We obtained several pinnal-tumor derived (PTD) cell lines and analyzed these for anchorage-independent growth, invasion into collagen matrices, tumorigenicity in athymic mice. Re-expression of either the short or a long isoform of Pcdh10 in two PTD lines counteracted malignancy in all assays. RNA-Seq analyses of these two PTD lines and their respective Pcdh10-rescued cell lines allowed to identify many interesting differentially expressed genes, which were largely different in the two cell families. Conclusions: A new mouse model was generated allowing for the first time to examine the remarkable tumor suppression activity of protocadherin-10 in vivo. Despite lacking several conserved motifs, the short isoform of Pcdh10 was fully active as tumor suppressor. Our model contributes to scrutinizing the complex molecular mechanisms of tumor initiation and progression upon PCDH10 silencing in many human cancers.
2022-03-12 | GSE198236 | GEO
Project description:BackgroundNonclustered mouse protocadherin genes (Pcdh) encode proteins with a typical single ectodomain and a cytoplasmic domain with conserved motifs completely different from those of classic cadherins. Alternative splice isoforms differ in the size of these cytoplasmic domains. In view of the compelling evidence for gene silencing of protocadherins in human tumors, we started investigations on Pcdh functions in mouse cancer models.MethodsFor Pcdh10, we generated two mouse lines: one with floxed exon 1, leading to complete Pcdh10 ablation upon Cre action, and one with floxed exons 2 and 3, leading to ablation of only the long isoforms of Pcdh10. In a mouse medulloblastoma model, we used GFAP-Cre action to locally ablate Pcdh10 in combination with Trp53 and Rb1 ablation. From auricular tumors, that also arose, we obtained tumor-derived cell lines, which were analyzed for malignancy in vitro and in vivo. By lentiviral transduction, we re-expressed Pcdh10 cDNAs. RNA-Seq analyses were performed on these cell families.ResultsSurprisingly, not only medulloblastomas were generated in our model but also tumors of tagged auricles (pinnae). For both tumor types, ablation of either all or only long isoforms of Pcdh10 aggravated the disease. We argued that the perichondrial stem cell compartment is at the origin of the pinnal tumors. Immunohistochemical analysis of these tumors revealed different subtypes. We obtained several pinnal-tumor derived (PTD) cell lines and analyzed these for anchorage-independent growth, invasion into collagen matrices, tumorigenicity in athymic mice. Re-expression of either the short or a long isoform of Pcdh10 in two PTD lines counteracted malignancy in all assays. RNA-Seq analyses of these two PTD lines and their respective Pcdh10-rescued cell lines allowed to identify many interesting differentially expressed genes, which were largely different in the two cell families.ConclusionsA new mouse model was generated allowing for the first time to examine the remarkable tumor suppression activity of protocadherin-10 in vivo. Despite lacking several conserved motifs, the short isoform of Pcdh10 was fully active as tumor suppressor. Our model contributes to scrutinizing the complex molecular mechanisms of tumor initiation and progression upon PCDH10 silencing in many human cancers.
| S-EPMC9040349 | biostudies-literature
Project description:Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour The data consists of five microarrays hybridized with methylated DNA immunoprecipitated from Wilms' tumours and from a normal foetal kidney control
2010-05-22 | E-GEOD-15027 | biostudies-arrayexpress
Project description:The nuclear receptor HNF4alpha is a master regulator of gene transcription in intestinal epithelial cells where P1 and P2 isoforms are expressed. HNF4alpha has been associated with colorectal cancer where its role remains controverisal since both tumor suppressor and oncogene characteristics have been observed. Evidences gathered from mouse models suggested however that this controversy on HNF4alpha function in colorectal cancer could be explained by the different functions of its two isoforms classes. In order to clarify this hypothesis in a human context, we downregulated the expression of HNF4alpha P1 or P2 isoforms using isoforms specific shRNA in the colorectal cancer cell line Caco2/15. Transcriptomic data were obtained by RNA-seq from these shRNA cell populations and compared to a non-target shRNA control.
2018-06-26 | GSE106378 | GEO
Project description:Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour
2009-02-27 | GSE15027 | GEO
Project description:Protocadherin 12 (Pcdh12) is a transmembrane adhesive protein with homophilic adhesive properties and expressed in endothelial cells, the glycogen trophoblast cells of the placenta, and the mesangial cells of kidney glomeruli. Pcdh12-deficient mice are alive although they show alterations in placenta development. To reveal Pcdh12-associated pathways, 45,000 - Affymetrix probe arrays were used on Pcdh12 knockout and control placentas. Keywords: Comparative gene knockout results
2008-06-30 | GSE7676 | GEO
Project description:Protocadherin 12 (Pcdh12) is a transmembrane adhesive protein with homophilic adhesive properties and expressed in endothelial cells, the glycogen trophoblast cells of the placenta, and the mesangial cells of kidney glomeruli. Pcdh12-deficient mice are alive although they show alterations in placenta development. To reveal Pcdh12-associated pathways, 45,000 - Affymetrix probe arrays were used on Pcdh12 knockout and control placentas. Experiment Overall Design: To identify genes whos expression was modified by Pcdh12 deficiency, we examined global gene expression profiles of whole E12.5 knockout placentas (Pcdh12 -l-) and their wild-type (WT â Pcdh12+l+ ) littermates, using the Affymetrix Murine Genome 430 2.0 microarrays. Gestation day 12 was chosen as it is the period at which placentas already formed distinct layers, but organogenesis is still very active. Total RNA was extracted from five Pcdh12 knockout embryos and five normal placentas. RNA were tested for integrity on Agilent 2100 BioAnalyzer, prior to cRNA synthesis and chip hybridization (performed by the Institute of Genetics and Molecular and Cellular Biology, Strasbourg, France).
2008-10-18 | E-GEOD-7676 | biostudies-arrayexpress
Project description:We identified cadherin superfamily member protocadherin 20 (PCDH20) as a crucial factor in CD using transcriptome sequencing. Thus,we elucidated the function and mechanisms of PCDH20 in gut homeostasis, barrier integrity, and CD development.
2023-06-14 | GSE230113 | GEO
Project description:The CNOT3 protein is a subunit of the CCR4-Not complex, a cytoplasmic protein complex mediating mRNA deadenylation as the first step in mRNA degradation. We recently identified CNOT3 loss-of-function mutations in patients with T-cell acute lymphoblastic leukemia (T-ALL). However, it is not clear yet how loss of this gene is involved in cancer development. Here we use different Drosophila melanogaster eye cancer models to study the potential tumor suppressor function of Not3, the CNOT3 orthologue, as well as other members of the CCR4-NOT complex. We show that not only Not3 but also the structural components Not1 and Not2, as well as the deadenylases Twin and Pop2 all behave as tumor suppressor genes. Moreover, RNA-sequencing analyses revealed that Not3 loss leads to increased expression levels of genes involved in DNA replication and ribosome biogenesis pathways, and that CycB is a Not3 target gene in our cancer models. Furthermore, we were able to confirm those results on human T-ALL cell lines, pointing out the conserved function of Not3 in both model systems and in tumor development. Together, our data establish a critical role for Not3 and the entire CCR4-NOT complex as a tumor suppressor.
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Project description:Intestinal epithelial cells are covered by the brush border, which consists of densely packed microvilli. The Intermicrovillar Adhesion Complex (IMAC) connects the microvilli and is required for proper organization of the brush border. The protocadherin CDHR5 is an important member of the IMAC, but it is unclear whether CDHR5 has mainly structural functions or is also involved in cellular signaling. This issue was resolved with a CDHR5 knockout mouse model. Intestinal epithelial cells were isolated from the small intestine of four wild-type and four CDHR5 knockout mice. Bulk RNA sequencing was performed to provide insight into the functions of CDHR5 in cellular signaling and gene regulation.
2023-04-13 | E-MTAB-12525 | biostudies-arrayexpress