A DLG1-ARHGAP31-CDC42 axis regulates the Wnt response in intestinal stem cells
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ABSTRACT:
PROVIDER: PRJNA816060 | ENA |
REPOSITORIES: ENA
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Project description:A central factor in maintenance of tissue integrity is the response of stem cells to variations in the levels of niche signals. In the gut, intestinal stem cells (ISCs) depend on Wnt ligands for self-renewal and proliferation. Transient increases in Wnt signaling promote regeneration after injury or in inflammatory bowel diseases, whereas constitutive activation of this pathway leads to colorectal cancer. Here, we report that Discs large 1 (Dlg1) is dispensable for polarity and cellular turnover during intestinal homeostasis; however, Dlg1 is required for ISC survival in the context of increased Wnt signaling. RNA sequencing (RNAseq) and genetic mouse models demonstrated that DLG1 regulates the cellular response to increased canonical Wnt signaling. This occurs via transcriptional regulation of Arhgap31, a GTPase-activating protein that deactivates CDC42, an effector of the non-canonical Wnt pathway. These findings reveal a DLG1-ARHGAP31-CDC42 axis that is essential for the ISC response to fluctuating niche Wnt signaling.
2023-01-15 | GSE198573 | GEO
Project description:Epithelial polarity is controlled by a polarity machinery including the Rho GTPase CDC42 and Scribble/PAR. By using intestinal stem cell (ISC)-specific deletion of CDC42 in Olfm4-IRES-eGFPCreERT2;CDC42flox/flox mice, we found that ISC-initiated CDC42 loss caused a drastic hyper-proliferation of transit amplifying (TA) cells and disrupted epithelial polarity. CDC42-null crypts displayed expanded TA cell and diminished ISC populations, accompanied by elevated hippo signaling via YAP/TAZ - Ereg and mTOR activation, independent from canonical Wnt signaling. YAP/TAZ conditional knockout restored the balance of ISC/TA cell populations and crypt proliferation but did not rescue the polarity in CDC42-null small intestine. mTOR or EGFR inhibitor treatment of CDC42 KO mice exhibited similar rescuing effects without affecting YAP/TAZ signaling. Inducible ablation of Scribble in intestinal epithelial cells mimics that of CDC42 KO defects including crypt hyperplasia and hippo signaling activation. Mammalian epithelial polarity regulates ISC and TA cell fate and proliferation via a hippo-Ereg-mTOR cascade.
2021-10-23 | GSE166736 | GEO
Project description:We show that Ror2 mediated non-canonical Wnt signaling in the dental mesenchyme plays a critical role in cell proliferation and thereby regulates root development size in mouse molars. Furthermore, Cdc42 acts as a potential downstream mediator of Ror2 signaling in root formation.
2020-11-13 | GSE161395 | GEO
Project description:The gut and liver have been recognized to mutually communicate through the biliary tract, portal vein and systemic circulation, but it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy, transcriptomics and proteomics profiling, we identified pigment epithelium-derived factor (PEDF), as a liver-derived soluble Wnt inhibitor, that can restrain intestinal stem cells (ISC) hyperproliferation for gut homeostasis by competing with Wnt ligands and suppressing Wnt/beta-catenin signaling pathway. In turn, microbial danger signals from intestinal inflammation can be sensed by the liver to repress PEDF production via peroxisome proliferator-activated receptor-alpha (PPAR alpha), liberating ISC proliferation to accelerate tissue repair in the gut. Further, treatment of mice with fenofibrate, a clinical agent of PPARalpha agonist for hypolipidemia enhances the susceptibility of colitis via PEDF activity. Therefore, we identified a distinct role of PEDF to calibrate ISC expansion for intestinal homeostasis via reciprocal interactions between the gut and liver.
2023-03-03 | MSV000091409 | MassIVE
Project description:Ror2-mediated non-canonical Wnt signaling regulates Cdc42 and cell proliferation during root development
| PRJNA678015 | ENA
Project description:The gut and liver are recognized to mutually communicate through the biliary tract, portal vein and systemic circulation, but it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy, transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, that restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/b-catenin signaling pathway. Further, we found that microbial danger signals occurring as a result of intestinal inflammation can be sensed by the liver to repress PEDF production via peroxisome proliferator-activated receptor-a (PPARa), liberating ISC proliferation to accelerate tissue repair in the gut. Finally, treatment of mice with fenofibrate, a clinical agent of PPARa agonist for hypolipidemia enhances the susceptibility of colitis via PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis via reciprocal interactions between the gut and liver.
2024-01-16 | GSE228829 | GEO
Project description:The function of the FAM83F protein, like the functions of many members of the FAM83 family, is poorly understood. Here we show that injection of Fam83f mRNA into Xenopus embryos causes axis duplication, a phenotype indicative of enhanced Wnt signalling. Consistent with this, overexpression of FAM83F activates Wnt signalling, whilst ablation of FAM83F from human colorectal cancer (CRC) cells attenuates it. We demonstrate that FAM83F is farnesylated and interacts and co-localises with CK1α at the plasma membrane. This interaction with CK1α is essential for FAM83F to activate Wnt signalling, and FAM83F mutants that do not interact with CK1α fail to induce axis duplication in Xenopus embryos and to activate Wnt signalling in cells. FAM83F acts upstream of GSK-3β, because the attenuation of Wnt signalling caused by loss of FAM83F can be rescued by GSK-3 inhibition. Introduction of a farnesyl-deficient mutant of FAM83F in cells through CRISPR/Cas9 genome editing redirects the FAM83F-CK1α complex away from the plasma membrane and significantly attenuates Wnt signalling, indicating that FAM83F exerts its effects on Wnt signalling at the plasma membrane.
2020-12-23 | PXD023121 | Pride
Project description:The crosstalk and balance regulation of Wnt-Notch have been known to be essential for cell fate decision and tissue regeneration, while how the balance is maintained and how the Wnt-Notch pathways are connected with the cell cycle regulation are still not clear. In the mouse model with accelerated aging phenotypes due to the loss of cell cycle inhibitor p21 function in Werner syndrome background, we observed the imbalance of Wnt-Notch signaling, along with the fast turnover of intestinal epithelia, which might cause the abnormal mobilization of stem cells, exhaust the stem cell reservoir, and result in the accelerated aging phenotypes. We revealed that the loss of p21 caused the shift of DREAM/Rb complex to MMB/E2F1 complex and the fast turnover of intestinal epithelia. Importantly, we identified the E2F1 as the transcriptional regulator for Notch1, which connected the p21-DREAM/MMB/Rb-E2F1 pathway with Wnt-Notch pathway. The overexpression of p21 rescued the imbalance of Wnt-Notch pathway. Our data identify p21 as an important factor in maintaining sequential mobilization, proliferation, and homeostasis of intestinal stem cells.
2023-12-10 | GSE248188 | GEO
Project description:Wnt/β-catenin signaling is essential for intestinal stem cell homeostasis and aberrant activation of this signaling leads to tumorigenesis. Here we report a function of YTHDF1, an mRNA m6A reader, in mediating β-catenin hyperactivation. Wnt signaling promotes YTHDF1 expression at the translational level. YTHDF1 is dispensable for normal intestinal development in mice while essential for intestinal regeneration. Ythdf1 knockout reduces the stemness of intestinal stem cells, which blocks Wnt-driven tumorigenesis. Genome-wide analysis identifies a subset of Wnt signaling components regulated by YTHDF1 in an m6A-dependent manner. Moreover, we demonstrate that YTHDF1 promotes the translation of TCF7L2/TCF4 to augment β-catenin activation. Targeting YTHDF1 in the established tumors leads to tumor shrinkage and prolonged survival. Together, our studies uncover YTHDF1 as an integral regulator of Wnt signaling at the translational level during intestinal tumorigenesis, which might serve as a promising target for colorectal cancer therapy.
2019-08-31 | GSE136664 | GEO
Project description:Background & Aims: Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions. Methods: We generated mice with intestinal epithelial-specific disruption of Cul4b (pVillin-cre; Cul4bfn/Y), inducible disruption of Cul4b (Lgr5-creERT2; Cul4bfn/Y, CAG-creERT2; Cul4bfn/Y) and their control (Cul4bfn/Y). Intestinal tissues were analyzed by histology, immunofluorescence, RNA sequencing and mass spectrum. Intestinal organoids deprived from mice with pVillin-Cre; Cul4bfn/Y, Lgr5-Cre; Cul4bfn/Y, Tg-Cul4b and their controls were used in assays to measure intestinal self-renewal, proliferation and differentiation. Wnt signaling and intestinal markers were analyzed by immunofluorescence and immunoblot assays. Differential proteins upon Cul4b ablation or Cul4b-interacting proteins were identified by mass spectrometry. Results: Cul4b specifically located at ISCs zone. Block of Cul4b impaired intestinal homeostasis maintenance by reduced self-renewal and proliferation. Transcriptome analysis revealed that Cul4b-null intestine lose ISC characterization and showed disturbed ISC niche. Mechanistically, reactivated Wnt pathway could recover intestinal dysfunction of Cul4b knockout mice. Analysis of differential total and ubiquitylated proteins uncovered the novel targeting substrate of Cullin-Ring ubiquitin ligase 4b (CRL4b), immunity-related GTPase family M member 1 (Irgm1) in intestine. Decreased Irgm1 rescued abnormally interferon signaling, overemphasized autophagy and downstream phosphate proteins in Cul4b knockout mice. Conclusion: We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.
2022-08-11 | PXD021528 | Pride