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- Title
FBW7 couples structural integrity with functional output of primary cilia.
- Authors
Petsouki, Eleni; Gerakopoulos, Vasileios; Szeto, Nicholas; Chang, Wenhan; Humphrey, Mary Beth; Tsiokas, Leonidas
- Abstract
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. Petsouki et al. dissect the importance of FBW7-mediated regulation of NDE1 and TALPID3 in mesenchymal stem cells (MSCs). They find that by modulating the abundance of negative (NDE1) and positive (TALPID3) cilia regulators, FBW7 contributes to both the assembly and signaling functions of primary cilia that are necessary for osteoblast differentiation.
- Subjects
CILIARY body diseases; MESENCHYMAL stem cells; OSTEOBLASTS; PROTEIN-protein interactions; CELL differentiation
- Publication
Communications Biology, 2021, Vol 4, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-021-02504-4