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

Xue Yuan, Jay Cao, Xiaoning He, Rosa Serra, Jun Qu, Xu Cao and Shuying Yang ()
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Xue Yuan: School of Dental Medicine, University of Buffalo, The State University of New York, 3435 Main Street, Buffalo, New York 14214, USA
Jay Cao: USDA Grand Forks Human Nutrition Research Center
Xiaoning He: School of Dental Medicine, University of Buffalo, The State University of New York, 3435 Main Street, Buffalo, New York 14214, USA
Rosa Serra: Developmental, and Integrative Biology, University of Alabama at Birmingham
Jun Qu: University at Buffalo, The State University of New York
Xu Cao: Johns Hopkins University School of Medicine
Shuying Yang: School of Dental Medicine, University of Buffalo, The State University of New York, 3435 Main Street, Buffalo, New York 14214, USA

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11024

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