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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...

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Autores principales: Petsouki, Eleni, Gerakopoulos, Vasileios, Szeto, Nicholas, Chang, Wenhan, Humphrey, Mary Beth, Tsiokas, Leonidas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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.
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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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