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Beta-Catenin protects the epidermis from mechanical stresses.

ABSTRACT: Many tissues in our body experience mechanical stresses caused by both internal and external forces. The skin, for example, must tolerate diverse mechanical insults. In this paper, we report a role for β-catenin in providing stability to epithelia under stress. Loss of β-catenin during epidermal development caused perinatal lethality. Mutant embryos up-regulated stress responses at sites of active morphogenesis, which became more widespread after the stresses associated with birth. In addition, selective loss of tight junctions occurred in focal regions. This was recapitulated in cultured β-catenin-null cells exposed to externally applied forces. In addition, mutant cells were defective in tension-induced engagement of adherens junctions. We found that β-catenin was required to recruit vinculin to the cell cortex and to strengthen the junction's association with the underlying cytoskeleton in response to tension. These data demonstrate that a complete understanding of the functions of cell adhesion proteins must take into account their roles in response to mechanical stresses.

SUBMITTER: Ray S

PROVIDER: S-EPMC3704987 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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beta-Catenin protects the epidermis from mechanical stresses.

Ray Samriddha S Foote Henry P HP Lechler Terry T

The Journal of cell biology 20130701 1

Many tissues in our body experience mechanical stresses caused by both internal and external forces. The skin, for example, must tolerate diverse mechanical insults. In this paper, we report a role for β-catenin in providing stability to epithelia under stress. Loss of β-catenin during epidermal development caused perinatal lethality. Mutant embryos up-regulated stress responses at sites of active morphogenesis, which became more widespread after the stresses associated with birth. In addition, ...[more]

PMID: 23816618

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Project description:Background & aimsPorphyrias result from anomalies of heme biosynthetic enzymes and can lead to cirrhosis and hepatocellular cancer. In mice, these diseases can be modeled by administration of a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes accumulation of porphyrin intermediates, resulting in hepatobiliary injury. Wnt/β-catenin signaling has been shown to be a modulatable target in models of biliary injury; thus, we investigated its role in DDC-driven injury.Methodsβ-Catenin (Ctnnb1) knockout (KO) mice, Wnt co-receptor KO mice, and littermate controls were fed a DDC diet for 2 weeks. β-Catenin was exogenously inhibited in hepatocytes by administering β-catenin dicer-substrate RNA (DsiRNA), conjugated to a lipid nanoparticle, to mice after DDC diet and then weekly for 4 weeks. In all experiments, serum and livers were collected; livers were analyzed by histology, western blotting, and real-time PCR. Porphyrin was measured by fluorescence, quantification of polarized light images, and liquid chromatography-mass spectrometry.ResultsDDC-fed mice lacking β-catenin or Wnt signaling had decreased liver injury compared to controls. Exogenous mice that underwent β-catenin suppression by DsiRNA during DDC feeding also showed less injury compared to control mice receiving lipid nanoparticles. Control livers contained extensive porphyrin deposits which were largely absent in mice lacking β-catenin signaling. Notably, we identified a network of key heme biosynthesis enzymes that are suppressed in the absence of β-catenin, preventing accumulation of toxic protoporphyrins. Additionally, mice lacking β-catenin exhibited fewer protein aggregates, improved proteasomal activity, and reduced induction of autophagy, all contributing to protection from injury.Conclusionsβ-Catenin inhibition, through its pleiotropic effects on metabolism, cell stress, and autophagy, represents a novel therapeutic approach for patients with porphyria.Lay summaryPorphyrias are disorders resulting from abnormalities in the steps that lead to heme production, which cause build-up of toxic by-products called porphyrins. Liver is commonly either a source or a target of excess porphyrins, and complications can range from minor abnormalities to liver failure. In this report, we inhibited Wnt/β-catenin signaling in an experimental model of porphyria, which resulted in decreased liver injury. Targeting β-catenin affected multiple components of the heme biosynthesis pathway, thus preventing build-up of porphyrin intermediates. Our study suggests that drugs inhibiting β-catenin activity could reduce the amount of porphyrin accumulation and help alleviate symptoms in patients with porphyria.

Dataset Information

Beta-Catenin protects the epidermis from mechanical stresses.

Publications

beta-Catenin protects the epidermis from mechanical stresses.

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