title: 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.
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University of Buffalo, The State University of New York, 3435 Main Street, Buffalo, New York 14214, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Yuan
authors.affiliation: USDA Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota 58202, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University of Buffalo, The State University of New York, 3435 Main Street, Buffalo, New York 14214, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Serra
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, New York 14214, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qu
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University of Buffalo, The State University of New York, 3435 Main Street, Buffalo, New York 14214, USA.|Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, University of Buffalo, The State University of New York, New York 14203, USA.
authors.forename: Shuying
authors.initials: S
authors.lastname: Yang
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002923:Cilia / Q000378:metabolism*; D017353:Gene Deletion; D053823:Hedgehog Proteins / Q000378:metabolism*; D018345:Mice, Knockout; D038081:Organogenesis; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D053823:Hedgehog Proteins; C558161:IFT80 protein, mouse; D020742:rhoA GTP-Binding Protein