title: Deletion of IFT80 Impairs Epiphyseal and Articular Cartilage Formation Due to Disruption of Chondrocyte Differentiation.
abstract: Intraflagellar transport proteins (IFT) play important roles in cilia formation and organ development. Partial loss of IFT80 function leads Jeune asphyxiating thoracic dystrophy (JATD) or short-rib polydactyly (SRP) syndrome type III, displaying narrow thoracic cavity and multiple cartilage anomalies. However, it is unknown how IFT80 regulates cartilage formation. To define the role and mechanism of IFT80 in chondrocyte function and cartilage formation, we generated a Col2α1; IFT80f/f mouse model by crossing IFT80f/f mice with inducible Col2α1-CreER mice, and deleted IFT80 in chondrocyte lineage by injection of tamoxifen into the mice in embryonic or postnatal stage. Loss of IFT80 in the embryonic stage resulted in short limbs at birth. Histological studies showed that IFT80-deficient mice have shortened cartilage with marked changes in cellular morphology and organization in the resting, proliferative, pre-hypertrophic, and hypertrophic zones. Moreover, deletion of IFT80 in the postnatal stage led to mouse stunted growth with shortened growth plate but thickened articular cartilage. Defects of ciliogenesis were found in the cartilage of IFT80-deficient mice and primary IFT80-deficient chondrocytes. Further study showed that chondrogenic differentiation was significantly inhibited in IFT80-deficient mice due to reduced hedgehog (Hh) signaling and increased Wnt signaling activities. These findings demonstrate that loss of IFT80 blocks chondrocyte differentiation by disruption of ciliogenesis and alteration of Hh and Wnt signaling transduction, which in turn alters epiphyseal and articular cartilage formation.
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University of Buffalo, State University of New York, Buffalo, NY, United States of America.
authors.forename: Xue
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University of Buffalo, State University of New York, Buffalo, NY, United States of America; Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, University of Buffalo, State University of New York, Buffalo, NY, United States of America.
authors.forename: Shuying
authors.initials: S
authors.lastname: Yang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002358:Cartilage, Articular / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D020219:Chondrogenesis; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D066186:Costal Cartilage / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D004838:Epiphyses; D017353:Gene Deletion; D053823:Hedgehog Proteins / Q000378:metabolism; D051379:Mice; D060449:Wnt Signaling Pathway
chemical_list: D002352:Carrier Proteins; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D053823:Hedgehog Proteins; C558161:IFT80 protein, mouse