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FBW7 couples structural integrity with functional output of primary cilia
Structural defects in primary cilia have robust effects in diverse tissues and systems. However, how disorders of ciliary length lead to functional outcomes are unknown. We examined the functional role of a ciliary length control mechanism of FBW7-mediated destruction of NDE1, in mesenchymal stem ce...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438042/ https://www.ncbi.nlm.nih.gov/pubmed/34518642 http://dx.doi.org/10.1038/s42003-021-02504-4 |
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author | Petsouki, Eleni Gerakopoulos, Vasileios Szeto, Nicholas Chang, Wenhan Humphrey, Mary Beth Tsiokas, Leonidas |
author_facet | Petsouki, Eleni Gerakopoulos, Vasileios Szeto, Nicholas Chang, Wenhan Humphrey, Mary Beth Tsiokas, Leonidas |
author_sort | Petsouki, Eleni |
collection | PubMed |
description | Structural defects in primary cilia have robust effects in diverse tissues and systems. However, how disorders of ciliary length lead to functional outcomes are unknown. We examined the functional role of a ciliary length control mechanism of FBW7-mediated destruction of NDE1, in mesenchymal stem cell (MSC) differentiation. We show that FBW7 functions as a master regulator of both negative (NDE1) and positive (TALPID3) regulators of ciliogenesis, with an overall positive net effect on primary cilia formation, MSC differentiation to osteoblasts, and bone architecture. Deletion of Fbxw7 suppresses ciliation, Hedgehog activity, and differentiation, which are partially rescued in Fbxw7/Nde1-null cells. We also show that NDE1, despite suppressing ciliogenesis, promotes MSC differentiation by increasing the activity of the Hedgehog pathway by direct binding and enhancing GLI2 activity in a cilia-independent manner. We propose that FBW7 controls a protein-protein interaction network coupling ciliary structure and function, which is essential for stem cell differentiation. |
format | Online Article Text |
id | pubmed-8438042 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84380422021-10-04 FBW7 couples structural integrity with functional output of primary cilia Petsouki, Eleni Gerakopoulos, Vasileios Szeto, Nicholas Chang, Wenhan Humphrey, Mary Beth Tsiokas, Leonidas Commun Biol Article Structural defects in primary cilia have robust effects in diverse tissues and systems. However, how disorders of ciliary length lead to functional outcomes are unknown. We examined the functional role of a ciliary length control mechanism of FBW7-mediated destruction of NDE1, in mesenchymal stem cell (MSC) differentiation. We show that FBW7 functions as a master regulator of both negative (NDE1) and positive (TALPID3) regulators of ciliogenesis, with an overall positive net effect on primary cilia formation, MSC differentiation to osteoblasts, and bone architecture. Deletion of Fbxw7 suppresses ciliation, Hedgehog activity, and differentiation, which are partially rescued in Fbxw7/Nde1-null cells. We also show that NDE1, despite suppressing ciliogenesis, promotes MSC differentiation by increasing the activity of the Hedgehog pathway by direct binding and enhancing GLI2 activity in a cilia-independent manner. We propose that FBW7 controls a protein-protein interaction network coupling ciliary structure and function, which is essential for stem cell differentiation. Nature Publishing Group UK 2021-09-13 /pmc/articles/PMC8438042/ /pubmed/34518642 http://dx.doi.org/10.1038/s42003-021-02504-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Petsouki, Eleni Gerakopoulos, Vasileios Szeto, Nicholas Chang, Wenhan Humphrey, Mary Beth Tsiokas, Leonidas FBW7 couples structural integrity with functional output of primary cilia |
title | FBW7 couples structural integrity with functional output of primary cilia |
title_full | FBW7 couples structural integrity with functional output of primary cilia |
title_fullStr | FBW7 couples structural integrity with functional output of primary cilia |
title_full_unstemmed | FBW7 couples structural integrity with functional output of primary cilia |
title_short | FBW7 couples structural integrity with functional output of primary cilia |
title_sort | fbw7 couples structural integrity with functional output of primary cilia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438042/ https://www.ncbi.nlm.nih.gov/pubmed/34518642 http://dx.doi.org/10.1038/s42003-021-02504-4 |
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