Dataset Information

Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish.

ABSTRACT: In the zebrafish embryo, the onset of blood flow generates fluid shear stress on endocardial cells, which are specialized endothelial cells that line the interior of the heart. High levels of fluid shear stress activate both Notch and Klf2 signaling, which play crucial roles in atrioventricular valvulogenesis. However, it remains unclear why only individual endocardial cells ingress into the cardiac jelly and initiate valvulogenesis. Here, we show that lateral inhibition between endocardial cells, mediated by Notch, singles out Delta-like-4-positive endocardial cells. These cells ingress into the cardiac jelly, where they form an abluminal cell population. Delta-like-4-positive cells ingress in response to Wnt9a, which is produced in parallel through an Erk5-Klf2-Wnt9a signaling cascade also activated by blood flow. Hence, mechanical stimulation activates parallel mechanosensitive signaling pathways that produce binary effects by driving endocardial cells toward either luminal or abluminal fates. Ultimately, these cell fate decisions sculpt cardiac valve leaflets.

SUBMITTER: Paolini A

PROVIDER: S-EPMC8511505 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish.

Paolini Alessio A Fontana Federica F Pham Van-Cuong VC Rödel Claudia Jasmin CJ Abdelilah-Seyfried Salim S

Cell reports 20211001 1

In the zebrafish embryo, the onset of blood flow generates fluid shear stress on endocardial cells, which are specialized endothelial cells that line the interior of the heart. High levels of fluid shear stress activate both Notch and Klf2 signaling, which play crucial roles in atrioventricular valvulogenesis. However, it remains unclear why only individual endocardial cells ingress into the cardiac jelly and initiate valvulogenesis. Here, we show that lateral inhibition between endocardial cell ...[more]

PMID: 34610316

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Project description:IntroductionThe Notch pathway plays an important role in many aspects of cancer biology and acts in a dichotomous way in bladder cancer. The mechanisms behind this behavior are still elusive. Here, we analyzed DLL4 and Notch receptor expression, interaction and downstream signaling in human bladder cancer cells.Materials and methodsThe expression levels of Notch pathway components (Notch1-4, DLL4, HES1, HEY1) were assessed in papillary (G1: RT-4) and non-papillary bladder cancer cell lines (G2-G4: RT-112, 647-V, T-24, KU-19-19, CAL-29) by qRT-PCR and immunofluorescence. Expression data were validated by analyzing data from open-source databases (CCLE; TCGA). The endogeneous interactions of Notch2/Notch3 receptors and the ligand DLL4 were studied by in situ proximity ligation assay. Activation of canonical Notch signaling was evaluated by stimulation with recombinant DLL4 protein.ResultsAll Notch targets were expressed, with Notch2 and Notch3 showing the highest expression levels. Endogeneous interactions between Notch2/3 and DLL4 were detected in all BCa cell lines. Amounts of Notch2/3-DLL4 complexes were high in RT-112 and CAL-29, while RT-4/647-V showed moderate and T-24, KU-19-19 low abundance. Proportion of (peri-) nuclear interaction complexes correlated negatively with Notch downstream targets. DLL4 stimulation resulted in canonical Notch pathway activation and increased tumor cell viability and proliferation in RT-4, 647-V, T-24 and KU-19-19 cells.DiscussionThe Notch signaling pathway can discriminate between different receptors and may play an essential role in the progression of bladder carcinoma. We demonstrated for the first time direct interactions between DLL4 and Notch2/3 associated to activation of canonical downstream Notch signaling and increased tumor cell behavior in human bladder cancer cells. Our data support the view that the Notch2/3-DLL4 axis plays an oncogenic role in bladder cancer. Further analyses of Notch signaling in bladder cancer can promote the development of tailored anti-DLL4/Notch bladder cancer therapies in the future.

Dataset Information

Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish.

Publications

Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish.

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