| First Author | Mahendram S | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 5 | Pages | e65320 |
| PubMed ID | 23724138 | Mgi Jnum | J:202157 |
| Mgi Id | MGI:5517605 | Doi | 10.1371/journal.pone.0065320 |
| Citation | Mahendram S, et al. (2013) Ectopic gamma-catenin expression partially mimics the effects of stabilized beta-catenin on embryonic stem cell differentiation. PLoS One 8(5):e65320 |
| abstractText | beta-catenin, an adherens junction component and key Wnt pathway effector, regulates numerous developmental processes and supports embryonic stem cell (ESC) pluripotency in specific contexts. The beta-catenin homologue gamma-catenin (also known as Plakoglobin) is a constituent of desmosomes and adherens junctions and may participate in Wnt signaling in certain situations. Here, we use beta-catenin((+/+)) and beta-catenin((-/-)) mouse embryonic stem cells (mESCs) to investigate the role of gamma-catenin in Wnt signaling and mESC differentiation. Although gamma-catenin protein is markedly stabilized upon inhibition or ablation of GSK-3 in wild-type (WT) mESCs, efficient silencing of its expression in these cells does not affect beta-catenin/TCF target gene activation after Wnt pathway stimulation. Nonetheless, knocking down gamma-catenin expression in WT mESCs appears to promote their exit from pluripotency in short-term differentiation assays. In beta-catenin((-/-)) mESCs, GSK-3 inhibition does not detectably alter cytosolic gamma-catenin levels and does not activate TCF target genes. Intriguingly, beta-catenin/TCF target genes are induced in beta-catenin((-/-)) mESCs overexpressing stabilized gamma-catenin and the ability of these genes to be activated upon GSK-3 inhibition is partially restored when wild-type gamma-catenin is overexpressed in these cells. This suggests that a critical threshold level of total catenin expression must be attained before there is sufficient signaling-competent gamma-catenin available to respond to GSK-3 inhibition and to regulate target genes as a consequence. WT mESCs stably overexpressing gamma-catenin exhibit robust Wnt pathway activation and display a block in tri-lineage differentiation that largely mimics that observed upon overexpression of beta-catenin. However, beta-catenin overexpression appears to be more effective than gamma-catenin overexpression in sustaining the retention of markers of naive pluripotency in cells that have been subjected to differentiation-inducing conditions. Collectively, our study reveals a function for gamma-catenin in the regulation of mESC differentiation and has implications for human cancers in which gamma-catenin is mutated and/or aberrantly expressed. |
