β-Catenin and FGFR2 Regulate Postnatal Rosette-Based Adrenocortical Morphogenesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE144503 | GEO | 2020/02/15
REPOSITORIES: GEO
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Project description:β-Catenin and FGFR2 Regulate Postnatal Rosette-Based Adrenocortical Morphogenesis
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Project description:Rosettes are widely used in epithelial morphogenesis during embryonic development and organogenesis. However, their role in postnatal development and adult tissue maintenance remains largely unknown. Here, we show zona glomerulosa cells in the adult adrenal cortex organize into rosettes through adherens junction-mediated constriction, and that rosette formation underlies the maturation of adrenal glomerular structure postnatally. Using genetic mouse models, we show loss of β-catenin results in disrupted adherens junctions, reduced rosette number, and dysmorphic glomeruli, whereas β-catenin stabilization leads to increased adherens junction abundance, more rosettes, and glomerular expansion. Furthermore, we uncover numerous known regulators of epithelial morphogenesis enriched in β-catenin-stabilized adrenals. Among these genes, we show Fgfr2 is required for adrenal rosette formation by regulating adherens junction abundance and aggregation. Together, our data provide an example of rosette-mediated postnatal tissue morphogenesis and a framework for studying the role of rosettes in adult zona glomerulosa tissue maintenance and function.
| S-EPMC7125176 | biostudies-literature
Project description:During development, multicellular rosettes serve as important cellular intermediates in the formation of diverse organ systems. Multicellular rosettes are transient epithelial structures that are defined by the apical constriction of cells towards the rosette center. Due to the important role these structures play during development, understanding the molecular mechanisms by which rosettes are formed and maintained is of high interest. Utilizing the zebrafish posterior lateral line primordium (pLLP) as a model system, we identify the RhoA GEF Mcf2lb as a regulator of rosette integrity. The pLLP is a group of ~150 cells that migrates along the zebrafish trunk and is organized into epithelial rosettes; these are deposited along the trunk and will differentiate into sensory organs called neuromasts (NMs). Using single-cell RNA sequencing and whole-mount in situ hybridization, we showed that mcf2lb is expressed in the pLLP during migration. Given the known role of RhoA in rosette formation, we asked whether Mcf2lb plays a role in regulating apical constriction of cells within rosettes. Live imaging and subsequent 3D analysis of mcf2lb mutant pLLP cells showed disrupted apical constriction and subsequent rosette organization. This in turn resulted in a unique posterior Lateral Line phenotype: an excess number of deposited NMs along the trunk of the zebrafish. Cell polarity markers ZO-1 and Par-3 were apically localized, indicating that pLLP cells are normally polarized. In contrast, signaling components that mediate apical constriction downstream of RhoA, Rock-2a and non-muscle Myosin II were diminished apically. Altogether our results suggest a model whereby Mcf2lb activates RhoA, which in turn activates downstream signaling machinery to induce and maintain apical constriction in cells incorporated into rosettes.
2023-04-19 | GSE229567 | GEO
Project description:Somatic hotspot mutations and structural amplifications and fusions affecting fibroblast growth factor receptor 2 (FGFR2) occur in multiple cancer types. However, clinical responses to FGFR inhibitors (FGFRi) have remained variable, emphasizing a need to better understand which FGFR2 alterations are oncogenic and targetable. Here we applied transposon-based screening and tumor modelling in mice to uncover truncation of exon (E) 18 of Fgfr2 as a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements (REs), E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing transcription of E18-truncated FGFR2 (FGFR2deltaE18). Somatic modelling in mice and human tumor cell lines using a compendium of FGFR2deltaE18 and full-length variants identified FGFR2deltaE18-truncation as potent single-driver alteration in cancer. Here we show the phosphoproteomic landscape of FGFR2 variants in murine epithelial cell (MEC) lines and mouse tumors. Global (STY) phosphoproteomics using IMAC and phosphotyrosine phosphoproteomics using pTyr IP’s are combined with DIA protein expression data to uncover oncogenic signaling of clinically-relevant FGFR2 variants.
2022-06-06 | PXD031711 | Pride
Project description:Genome-wide association studies have identified a locus within the second intron of the FGFR2 gene that is consistently the most strongly associated with estrogen receptor-poisive breast cancer risk. However, we know little about the mechanisms by which the FGFR2 locus mediates risk or the pathways in which multiple risk loci may combine to cause disease. Previously, a systems biology approach was adopted to elucidate the regulatory networks operating in MCF-7 breast cancer cells in order to examine the role of FGFR2 in mediating risk. Here, the same approach has been employed using MCF-7 cells that have been treated with siRNA directed against FGFR2, in order to knock-down FGFR2 expression, to confirm that the differential gene expression that we see when FGF10 signalling is perturbed, on a background of estrogen signalling, is mediated via FGFR2 stimulation.
2016-02-01 | GSE74146 | GEO
Project description:The first in vitro tests for developmental toxicity made use of rodent cells. Newer teratology tests, e.g. developed during the ESNATS project, use human cells and measure mechanistic endpoints (such as transcriptome changes). However, the toxicological implications of mechanistic parameters are hard to judge, without functional/morphological endpoints. To address this issue, we developed a new version of the human stem cell-based test STOP-tox(UKN). For this purpose, the capacity of the cells to self-organize to neural rosettes was assessed as functional endpoint: pluripotent stem cells were allowed to differentiate to neuroepithelial cells for six days in the presence or absence of toxicants. Then, both transcriptome changes were measured (standard STOP-tox(UKN)), and cells were allowed to form rosettes. After optimization of staining methods, an imaging algorithm for rosette quantification was implemented and used for an automated rosette formation assay (RoFA). Neural tube toxicants (like valproic acid), which are known to disturb human development at stages when rosette-forming cells are present, were used as positive controls. Established toxicants led to distinctly different tissue organization and differentiation stages. RoFA outcome and transcript changes largely correlated concerning (i) the concentration-dependence, (ii) the time-dependence, and (iii) the set of positive hits identified amongst 24 potential toxicants. Using such comparative data, a prediction model for the RoFA was developed. The comparative analysis was also used to identify gene dysregulations that are particularly predictive for disturbed rosette formation. This ‘RoFA predictor gene set’ may be used for a simplified and less costly setup of the STOP-tox(UKN) assay.
2019-12-03 | GSE141253 | GEO
Project description:Genome-wide association studies for breast cancer have identified over 80 different risk regions in the genome, with the FGFR2 locus consistently identified as the most strongly associated locus. However, we know little about the mechanisms by which the FGFR2 locus mediates risk or the pathways in which multiple risk loci may combine to cause disease. Here we use a systems biology approach to elucidate the regulatory networks operating in breast cancer and examine the role of FGFR2 in mediating risk. Using model systems we identify FGFR2-regulated genes and, combining variant set enrichment and eQTL analysis, show that these are preferentially linked to breast cancer risk loci. Our results support the concept that cancer-risk associated genes cluster in pathways
2013-07-17 | GSE48925 | GEO
Project description:Genome-wide association studies for breast cancer have identified over 80 different risk regions in the genome, with the FGFR2 locus consistently identified as the most strongly associated locus. However, we know little about the mechanisms by which the FGFR2 locus mediates risk or the pathways in which multiple risk loci may combine to cause disease. Here we use a systems biology approach to elucidate the regulatory networks operating in breast cancer and examine the role of FGFR2 in mediating risk. Using model systems we identify FGFR2-regulated genes and, combining variant set enrichment and eQTL analysis, show that these are preferentially linked to breast cancer risk loci. Our results support the concept that cancer-risk associated genes cluster in pathways The data consists of 71 microarray samples from MCF-7 cells treated under different conditions, at 3 time points (0, 6 and 24 h) in order to perturb FGFR2 signalling using the iF2 construct system. The data have been pre-processed in R using the beadarray package, and are presented in the form of log2 expression values. The experiment was carried out on 6 Humanv4 BeadChips using 12 samples per BeadChip. The original arrays contain 48324 features, with a mean of 22 beads per feature (Standard Deviation of 5)
2013-07-17 | E-GEOD-48925 | biostudies-arrayexpress
Project description:The Arabidopsis rosette core can display full resistance against Botrytis cinerea. To reveal potential players in this resistance, the transcriptome of the Arabidopsis rosette core was determined.
2019-04-09 | GSE129452 | GEO
Project description:Fibroblast Growth Factor (FGF) dependent signalling is frequently activated in cancer by a variety of different mechanisms. However, the downstream signal transduction pathways involved are poorly characterised. Here a quantitative differential phosphoproteomics approach, SILAC, is applied to identify FGF-regulated phosphorylation events in two triple- negative breast tumour cell lines, MFM223 and SUM52PE, that exhibit amplified expression of FGF receptor 2 (FGFR2) and are dependent on continued FGFR2 signalling for cell viability. Comparative Gene Ontology proteome analysis revealed that SUM52PE cells were enriched in proteins associated with cell metabolism and MFM223 cells enriched in proteins associated with cell adhesion and migration. FGFR2 inhibition by SU5402 impacts a significant fraction of the observed phosphoproteome of these cells. This study expands the known landscape of FGF signalling and identifies many new targets for functional investigation. FGF signalling pathways are found to be flexible in architecture as both shared, and divergent, responses to inhibition of FGFR2 kinase activity in the canonical RAF/MAPK/ERK/RSK and PI3K/AKT/PDK/mTOR/S6K pathways are identified. Inhibition of phosphorylation-dependent negative-feedback pathways is observed, defining mechanisms of intrinsic resistance to FGFR2 inhibition. These findings have implications for the therapeutic application of FGFR inhibitors as they identify both common and divergent responses in cells harbouring the same genetic lesion and pathways of drug resistance.
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