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.
Structural defects in cilia have robust effects in diverse tissues and systems. However, how ciliary length changes influence signaling output are unknown. Here, we examined the functional role of a ciliary length control mechanism whereby FBW7-mediated destruction of NDE1 positively regulated ciliary length, in mesenchymal stem cell 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 cilia formation, MSC differentiation, and bone architecture. Deletion of Fbxw7 suppresses ciliation, Hedgehog activity, and differentiation, which are rescued in Fbxw7/Nde1-null cells. However, despite formation of abnormally long cilia in Nde1-null cells, MSC differentiation is suppressed. NDE1 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 ciliary structure-function coupling is determined by intricate interactions of structural and functional proteins.
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