Ciliary IFT80 Balances Canonical Versus Non-canonical Hedgehog Signalling for Osteoblast Differentiation

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Mar 22

PMID 26996322

Citations 73

Authors

Xue Yuan

Jay Cao

Xiaoning He

Rosa Serra

Jun Qu

Xu Cao

Shuying Yang

Affiliations

Soon will be listed here.

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.

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