title: Ift88 regulates Hedgehog signaling, Sfrp5 expression, and β-catenin activity in post-natal growth plate.
abstract: Primary cilia are present on most cell types including chondrocytes. Dysfunction of primary cilia results in pleiotropic symptoms including skeletal dysplasia. Previously, we showed that deletion of Ift88 and subsequent depletion of primary cilia from chondrocytes resulted in disorganized columnar structure and early loss of growth plate. To understand underlying mechanisms whereby Ift88 regulates growth plate function, we compared gene expression profiles in normal and Ift88 deleted growth plates. Pathway analysis indicated that Hedgehog (Hh) signaling was the most affected pathway in mutant growth plate. Expression of the Wnt antagonist, Sfrp5, was also down-regulated. In addition, Sfrp5 was up-regulated by Shh in rib chondrocytes and regulation of Sfrp5 by Shh was attenuated in mutant cells. This result suggests Sfrp5 is a downstream target of Hh and that Ift88 regulates its expression. Sfrp5 is an extracellular antagonist of Wnt signaling. We observed an increase in Wnt/β-catenin signaling specifically in flat columnar cells of the growth plate in Ift88 mutant mice as measured by increased expression of Axin2 and Lef1 as well as increased nuclear localization of β-catenin. We propose that Ift88 and primary cilia regulate expression of Sfrp5 and Wnt signaling pathways in growth plate via regulation of Ihh signaling.
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, 1918 University Blvd., 660 MCLM Birmingham, Alabama 35294-0005, USA.
authors.forename: Ching-Fang
authors.initials: CF
authors.lastname: Chang
authors.forename: Rosa
authors.initials: R
authors.lastname: Serra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D012272:Ribs / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D059467:Transcriptome / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C487972:Sfrp5 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C465570:Shh protein, mouse; C490898:Tg737Rpw protein, mouse