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Regulation of epithelial-mesenchymal transition and organoid morphogenesis by a novel TGFβ-TCF7L2 isoform-specific signaling pathway
Alternative splicing contributes to diversification of gene function, yet consequences of splicing on functions of specific gene products is poorly understood. The major transcription factor TCF7L2 undergoes alternative splicing but the biological significance of TCF7L2 isoforms has remained largely...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447769/ https://www.ncbi.nlm.nih.gov/pubmed/32843642 http://dx.doi.org/10.1038/s41419-020-02905-z |
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author | Karve, Kunal Netherton, Stuart Deng, Lili Bonni, Azad Bonni, Shirin |
author_facet | Karve, Kunal Netherton, Stuart Deng, Lili Bonni, Azad Bonni, Shirin |
author_sort | Karve, Kunal |
collection | PubMed |
description | Alternative splicing contributes to diversification of gene function, yet consequences of splicing on functions of specific gene products is poorly understood. The major transcription factor TCF7L2 undergoes alternative splicing but the biological significance of TCF7L2 isoforms has remained largely to be elucidated. Here, we find that the TCF7L2 E-isoforms maintain, whereas the M and S isoforms disrupt morphogenesis of 3D-epithelial cell-derived organoids via regulation of epithelial-mesenchymal transition (EMT). Remarkably, TCF7L2E2 antagonizes, whereas TCF7L2M2/S2 promotes EMT-like effects in epithelial cells induced by transforming growth factor beta (TGFβ) signaling. In addition, we find TGFβ signaling reduces the proportion of TCF7L2E to TCF7L2M/S protein in cells undergoing EMT. We also find that TCF7L2 operates via TGFβ-Smad3 signaling to regulate EMT. Collectively, our findings unveil novel isoform-specific functions for the major transcription factor TCF7L2 and provide novel links between TCF7L2 and TGFβ signaling in the control of EMT-like responses and epithelial tissue morphogenesis. |
format | Online Article Text |
id | pubmed-7447769 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74477692020-09-02 Regulation of epithelial-mesenchymal transition and organoid morphogenesis by a novel TGFβ-TCF7L2 isoform-specific signaling pathway Karve, Kunal Netherton, Stuart Deng, Lili Bonni, Azad Bonni, Shirin Cell Death Dis Article Alternative splicing contributes to diversification of gene function, yet consequences of splicing on functions of specific gene products is poorly understood. The major transcription factor TCF7L2 undergoes alternative splicing but the biological significance of TCF7L2 isoforms has remained largely to be elucidated. Here, we find that the TCF7L2 E-isoforms maintain, whereas the M and S isoforms disrupt morphogenesis of 3D-epithelial cell-derived organoids via regulation of epithelial-mesenchymal transition (EMT). Remarkably, TCF7L2E2 antagonizes, whereas TCF7L2M2/S2 promotes EMT-like effects in epithelial cells induced by transforming growth factor beta (TGFβ) signaling. In addition, we find TGFβ signaling reduces the proportion of TCF7L2E to TCF7L2M/S protein in cells undergoing EMT. We also find that TCF7L2 operates via TGFβ-Smad3 signaling to regulate EMT. Collectively, our findings unveil novel isoform-specific functions for the major transcription factor TCF7L2 and provide novel links between TCF7L2 and TGFβ signaling in the control of EMT-like responses and epithelial tissue morphogenesis. Nature Publishing Group UK 2020-08-25 /pmc/articles/PMC7447769/ /pubmed/32843642 http://dx.doi.org/10.1038/s41419-020-02905-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Karve, Kunal Netherton, Stuart Deng, Lili Bonni, Azad Bonni, Shirin Regulation of epithelial-mesenchymal transition and organoid morphogenesis by a novel TGFβ-TCF7L2 isoform-specific signaling pathway |
title | Regulation of epithelial-mesenchymal transition and organoid morphogenesis by a novel TGFβ-TCF7L2 isoform-specific signaling pathway |
title_full | Regulation of epithelial-mesenchymal transition and organoid morphogenesis by a novel TGFβ-TCF7L2 isoform-specific signaling pathway |
title_fullStr | Regulation of epithelial-mesenchymal transition and organoid morphogenesis by a novel TGFβ-TCF7L2 isoform-specific signaling pathway |
title_full_unstemmed | Regulation of epithelial-mesenchymal transition and organoid morphogenesis by a novel TGFβ-TCF7L2 isoform-specific signaling pathway |
title_short | Regulation of epithelial-mesenchymal transition and organoid morphogenesis by a novel TGFβ-TCF7L2 isoform-specific signaling pathway |
title_sort | regulation of epithelial-mesenchymal transition and organoid morphogenesis by a novel tgfβ-tcf7l2 isoform-specific signaling pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447769/ https://www.ncbi.nlm.nih.gov/pubmed/32843642 http://dx.doi.org/10.1038/s41419-020-02905-z |
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