title: The transcription factor Foxc1 is necessary for Ihh-Gli2-regulated endochondral ossification.
abstract: Indian hedgehog (Ihh) regulates endochondral ossification in both a parathyroid hormone-related protein (PTHrP)-dependent and -independent manner by activating transcriptional mediator Gli2. However, the molecular mechanisms underlying these processes remain elusive. Here by using in vivo microarray analysis, we identify forkhead box C1 (Foxc1) as a transcriptional partner of Gli2. Foxc1 stimulates expression of Ihh target genes, including PTHrP and Col10a1, through its physical and functional interaction with Gli2. Conversely, a dominant negative Foxc1 inhibits the Ihh target gene expression. In a spontaneous loss of Foxc1 function mouse (Foxc1(ch/ch)), endochondral ossification is delayed and the expression of Ihh target genes inhibited. Moreover, the pathological Foxc1 missense mutation observed in the Axenfeld-Rieger syndrome impairs Gli2-Foxc1 association as well as Ihh function. Our findings suggest that Foxc1 is an important transcriptional partner of Ihh-Gli2 signalling during endochondral ossification, and that disruption of the Foxc1-Gli2 interaction causes skeletal abnormalities observed in the Axenfeld-Rieger syndrome.
authors: 1] Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan [2] Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors: Michiko
authors: M
authors: Yoshida
authors: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan.
authors: Kenji
authors: K
authors: Hata
authors: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan.
authors: Rikako
authors: R
authors: Takashima
authors: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan.
authors: Koichiro
authors: K
authors: Ono
authors: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan.
authors: Eriko
authors: E
authors: Nakamura
authors: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan.
authors: Yoshifumi
authors: Y
authors: Takahata
authors: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan.
authors: Tomohiko
authors: T
authors: Murakami
authors: Section of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
authors: Sachiko
authors: S
authors: Iseki
authors: Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors: Teruko
authors: T
authors: Takano-Yamamoto
authors: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan.
authors: Riko
authors: R
authors: Nishimura
authors: 1] Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan [2] Division of Hematology/Oncology, Indiana University School of Medicine, Walther Hall, R3-C321D, 980 West Walnut Street, Indianapolis, Indiana 46202, USA.
authors: Toshiyuki
authors: T
authors: Yoneda
mesh_terms: D000818:Animals; D000869:Anterior Eye Segment / Q000002:abnormalities*; D019556:COS Cells; D002522:Chlorocebus aethiops; D019902:Chondrocytes / Q000378:metabolism*; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005124:Eye Abnormalities / Q000235:genetics*; D015785:Eye Diseases, Hereditary; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010012:Osteogenesis / Q000235:genetics*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015533:Transcriptional Activation; D000075746:Zinc Finger Protein Gli2
chemical_list: C570620:Col10a1 protein, mouse; D024121:Collagen Type X; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D044162:Parathyroid Hormone-Related Protein; D000075746:Zinc Finger Protein Gli2; C514061:ihh protein, mouse