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The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification

Author

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  • Michiko Yoshida

    (Osaka University Graduate School of Dentistry
    Tohoku University Graduate School of Dentistry)

  • Kenji Hata

    (Osaka University Graduate School of Dentistry)

  • Rikako Takashima

    (Osaka University Graduate School of Dentistry)

  • Koichiro Ono

    (Osaka University Graduate School of Dentistry)

  • Eriko Nakamura

    (Osaka University Graduate School of Dentistry)

  • Yoshifumi Takahata

    (Osaka University Graduate School of Dentistry)

  • Tomohiko Murakami

    (Osaka University Graduate School of Dentistry)

  • Sachiko Iseki

    (Section of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University)

  • Teruko Takano-Yamamoto

    (Tohoku University Graduate School of Dentistry)

  • Riko Nishimura

    (Osaka University Graduate School of Dentistry)

  • Toshiyuki Yoneda

    (Osaka University Graduate School of Dentistry
    Indiana University School of Medicine)

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 (Foxc1ch/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.

Suggested Citation

  • Michiko Yoshida & Kenji Hata & Rikako Takashima & Koichiro Ono & Eriko Nakamura & Yoshifumi Takahata & Tomohiko Murakami & Sachiko Iseki & Teruko Takano-Yamamoto & Riko Nishimura & Toshiyuki Yoneda, 2015. "The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification," Nature Communications, Nature, vol. 6(1), pages 1-15, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7653
    DOI: 10.1038/ncomms7653
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    Cited by:

    1. Fabrice Darbellay & Anna Ramisch & Lucille Lopez-Delisle & Michael Kosicki & Antonella Rauseo & Zahra Jouini & Axel Visel & Guillaume Andrey, 2024. "Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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