Ciliary IFT80 balances canonical versus non-canonical hedgehog signalling for osteoblast differentiation

Abstract

Intraflagellar transport proteins (IFT) are required for hedgehog (Hh) signalling transduction that is essential for bone development, however, how IFT proteins regulate Hh signalling in osteoblasts (OBs) remains unclear. Here we show that deletion of ciliary IFT80 in OB precursor cells (OPC) in mice results in growth retardation and markedly decreased bone mass with impaired OB differentiation. Loss of IFT80 blocks canonical Hh–Gli signalling via disrupting Smo ciliary localization, but elevates non-canonical Hh–Gαi–RhoA–stress fibre signalling by increasing Smo and Gαi binding. Inhibition of RhoA and ROCK activity partially restores osteogenic differentiation of IFT80-deficient OPCs by inhibiting non-canonical Hh–RhoA–Cofilin/MLC2 signalling. Cytochalasin D, an actin destabilizer, dramatically restores OB differentiation of IFT80-deficient OPCs by disrupting actin stress fibres and promoting cilia formation and Hh–Gli signalling. These findings reveal that IFT80 is required for OB differentiation by balancing between canonical Hh–Gli and non-canonical Hh–Gαi–RhoA pathways and highlight IFT80 as a therapeutic target for craniofacial and skeletal abnormalities.

Primary Cilia and Intraflagellar Transport Proteins in Bone and Cartilage

“…These findings suggest that IFT80 regulates osteoblast differentiation by balancing canonical Hh-Gli and noncanonical Hh-Gαi-RhoA pathways (Yuan et al 2016).…”

“…Most recently, we found the novel role of IFT80 in skeletal development using an IFT80 conditional knockout mouse model (Yuan et al 2016). Osx-Cre-mediated IFT80 deletion in osteoblast precursor cells leads to markedly decreased bone mass with impaired osteoblast differentiation.…”

“…OSX-Cre;IFT80 f/f mice show decreased bone mass with impaired osteoblast differentiation; loss of IFT80 blocks canonical Hh-Gli signaling transduction while elevating noncanonical Hh-Gαi-RhoA signaling Yuan et al 2016 …”

Expression and prognostic significance of MYL9 in esophageal squamous cell carcinoma

“…MYL9 expression levels were most closely related to tumor differentiation among the conventional clinicopathological characteristics of ESCC. The Rho/Rho-associated serine-threonine protein kinase (ROCK) pathway is involved in the differentiation of osteoblasts, lung fibroblasts, and other cell types [29, 30]. Inhibiting RhoA and ROCK activity partially restoreds osteogenic differentiation by inhibiting Hh-RhoA-Cofilin/MYL9 signaling [29].…”

“…The Rho/Rho-associated serine-threonine protein kinase (ROCK) pathway is involved in the differentiation of osteoblasts, lung fibroblasts, and other cell types [29, 30]. Inhibiting RhoA and ROCK activity partially restoreds osteogenic differentiation by inhibiting Hh-RhoA-Cofilin/MYL9 signaling [29]. Nevertheless, the effect of MYL9 on tumor cell differentiation has not been investigated.…”