2. Academic Validation
  3. FBW7 couples structural integrity with functional output of primary cilia

FBW7 couples structural integrity with functional output of primary cilia

  • Commun Biol. 2021 Sep 13;4(1):1066. doi: 10.1038/s42003-021-02504-4.
Eleni Petsouki 1,  Vasileios Gerakopoulos 1,  Nicholas Szeto 2,  Wenhan Chang 2,  Mary Beth Humphrey 3 4,  Leonidas Tsiokas 5
Affiliations

Affiliations

  • 1 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • 2 Department of Medicine, Division of Endocrinology and Metabolism, University of California San Francisco, San Francisco, CA, USA.
  • 3 Department of Internal Medicine, Division of Rheumatology, Immunology, and Allergy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • 4 Department of Medicine, Oklahoma City Veteran's Affairs Medical Center, Oklahoma City, OK, USA.
  • 5 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. ltsiokas@ouhsc.edu.
PMID: 34518642 DOI: 10.1038/s42003-021-02504-4
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.

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