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

Xue Yuan; Jay Cao; Xiaoning He; Rosa Serra; Jun Qu; Xu Cao; Shuying Yang

doi:10.1038/ncomms11024

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

Xue Yuan, Jay Cao, Xiaoning He, Rosa Serra, Jun Qu, Xu Cao, Shuying Yang

School of Medicine

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

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.

Original language	English (US)
Article number	11024
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11024
State	Published - Mar 21 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms11024

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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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AU - He, Xiaoning

AU - Serra, Rosa

AU - Qu, Jun

AU - Cao, Xu

AU - Yang, Shuying

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

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