FBW7 couples structural integrity with functional output of primary cilia

Eleni Petsouki,Wenhan Chang,Leonidas Tsiokas,Nicholas Szeto,Mary Beth Humphrey,Vasileios Gerakopoulos

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.

Highlights

Structural defects in primary cilia have robust effects in diverse tissues and systems
Serum bone-specific alkaline phosphatase levels (BALP) (Fig. 1h and Supplementary Data 1), but not Tartrate resistant acid phosphatase (TRAcP) (Fig. 1i and Supplementary Data 1), were reduced in mutant mice indicating that reduced bone mass may have been primarily caused by reduced osteoblast differentiation and/or function
While it is known that abnormally long or short cilia can result in severe phenotypes in diverse tissues and systems, it is not clear how changes in ciliary length can influence signaling output resulting in these robust phenotypes

Summary

Introduction

Structural defects in primary cilia have robust effects in diverse tissues and systems. We examined the functional role of a ciliary length control mechanism of FBW7-mediated destruction of NDE1, in mesenchymal stem cell (MSC) differentiation. 1234567890():,; The primary cilium is a solitary, antenna-like organelle protruding into the extracellular space[1] It is present in virtually all cell types of the human body functioning as a signaling center for receptor tyrosine kinases, G protein coupled receptors, the Hedgehog, Notch, and Wnt pathways[2,3,4,5,6]. Exact effects of primary cilia per se, ciliary length, and contribution of cilia-based signaling and their underlying mechanisms in MSC differentiation are not completely understood. FBW7 has established roles in maintenance, self-renewal, and differentiation of several adult stem cell types including cancer initiating cells[26,27], but the contribution of primary cilia to these effects is unknown. We previously showed that FBW7 mediates its effect on ciliary length by the timely destruction of NDE1, a negative regulator of ciliogenesis[28]

Methods

Results

Conclusion