Cadherin adhesion complexes direct cell aggregation in the epithelial transition of Wnt-induced nephron progenitor cells
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ABSTRACT:
PROVIDER: PRJNA973005 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24579645_1.fastq.gz | Fastqsanger.gz | |||
| SRR24579645_2.fastq.gz | Fastqsanger.gz | |||
| SRR24579646_1.fastq.gz | Fastqsanger.gz | |||
| SRR24579646_2.fastq.gz | Fastqsanger.gz | |||
| SRR24579647_1.fastq.gz | Fastqsanger.gz |
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Project description:The aggregation of nephron progenitor cells (NPC) is required to form the nephron precursor renal vesicle (RV) as they undergo the mesenchymal-to-epithelial transition (MET). Canonical Wnt signaling regulates the MET of NPCs via the effector molecule β-catenin. β-catenin acts as a transcriptional co-activator during the differentiation of NPCs, however, if it has any role as an adhesion regulating molecule via the cadherin-catenin complex is currently unknown. Using in vitro NPC culture system with gene editing and modulated Wnt signaling input, we investigated the morphological transition of NPCs and its underlying mechanism modeling the initial step of the MET in vivo. Increasing Wnt signaling input with the small molecule agonist CHIR resulted in the aggregation of NPCs similar to the generation of the nephron anlagen. By removing β- and α-catenin from the NPCs, NPCs are sorted out from these aggregates, demonstrating the key role of the cadherin-catenin complex in the aggregation. β-catenin was essential for the induction, however, the removal of α-catenin did not affect the transcriptional profile of NPCs. Removal of extracellular Ca2+ resulted in the transient loss of cell-cell contacts suggesting the role of cadherins in the aggregation process. The analysis of in vitro bulk RNA-seq cadherin expression profile matched the in vivo cadherin expression profile determined by single-cell RNA-seq. The combined removal of pre-existing and inducible cadherins phenocopied the results of β- and α-catenin KO experiments highlighting the crucial role of the cadherin-catenin complex by multiple lines of evidence. Notably, the induction of NPCs is independent of their aggregation. The in vitro modeling of nephron development provides a mechanistic understanding how cell adhesion is regulated via the cadherin-catenin complex during nephrogenesis.
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Project description:Wnt/β-catenin signaling is a highly conserved molecular pathway that plays a crucial role in stem/progenitor systems and cancer. β-catenin, the main Wnt pathway effector, has two pools within a cell: one for cell-cell adhesion at the membrane and the other for transcriptional functions in the nucleus. However, the mechanism by which β-catenin mediates both roles remain unclear. The tightly controlled, well characterized system of nephrogenesis is an ideal model to decouple the roles of β-catenin at the membrane and in the nucleus. In kidney development, a delicate balance of nephron progenitor cell self-renewal and differentiation is required for the mesenchymal to epithelial transition (MET) in nephrogenesis and is driven by Wnt/β-catenin signaling. Given an ability to isolate and manipulate large numbers of NPCs in tissue culture, we can dissect the dual nature of β-catenin as a transcriptional activator and component of a cell membrane complex in adhesion. We pioneered a method using CRISPR/Cas9 gene editing to rapidly remove β-catenin, Tcf/Lef factors and simultaneous cadherin genes in primary NPCs. We have characterized the effects of modulating β-catenin and integrated RNA-seq results from β-catenin’s removal with mouse ChIP-seq and mouse single cell RNA -seq data. Functional analysis of β-catenin removal provides strong evidence for β-catenin regulation of NPC proliferation, independent of a direct Lef/Tcf associated transcriptional program. Together these data suggest β-catenin mediates aggregation, the first step in MET, through β-catenin mediated cell adhesion complexes while simultaneous transcriptional activation within these structures initiates the nephrogenic program. The studies provide new insight into the direct transcriptional role of Lef/Tcf/β-catenin complexes associated with the initiation of a nephron forming program. Overall, this study enhances an understanding of the molecular mechanisms underlying kidney development and the dual nature of β-catenin stem/progenitor systems at large.
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Project description:Psoriasis patients exhibit an increased risk of death by cardiovascular disease (CVD) and have elevated levels of circulating intermediate (CD14++CD16+) monocytes. This elevation could represent evidence of monocyte dysfunction in psoriasis patients at risk of CVD, as increases in circulating CD14++CD16+ monocytes are predictive of myocardial infarction and death. An elevation in the CD14++CD16+ cell population has been previously reported in patients with psoriatic disease, which has been confirmed in the cohort of our human psoriasis patients. CD16 expression was induced in CD14++CD16neg classical monocytes following plastic adhesion, which also elicited enhanced β2 but not β1 integrin surface expression, suggesting increased adhesive capacity. Indeed, we found that psoriasis patients have increased monocyte aggregation among circulating PBMCs which is recapitulated in the KC-Tie2 murine model of psoriasis. Visualization of human monocyte aggregates using imaging cytometry revealed that classical CD14++CD16neg monocytes are the predominant cell type participating in these aggregate pairs. Many of these pairs also included CD16+ monocytes, which could account for apparent elevations of intermediate monocytes. Additionally, intermediate monocytes and monocyte aggregates were the predominant cell type to adhere to TNF-α and IL-17A-stimulated dermal endothelium. Ingenuity Pathway Analysis (IPA) demonstrated that monocyte aggregates have a distinct transcriptional profile from singlet monocytes and monocytes following plastic adhesion, suggesting that circulating monocyte responses to aggregation are not fully accounted for by homotypic adhesion, and that further factors influence their functionality. qRT-PCR Gene Expression Profiling - 30 Samples Analyzed, 10 biological replicates, 10 Control Samples, 20 Test Samples
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