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

Michiko Yoshida, Kenji Hata (), Rikako Takashima, Koichiro Ono, Eriko Nakamura, Yoshifumi Takahata, Tomohiko Murakami, Sachiko Iseki, Teruko Takano-Yamamoto, Riko Nishimura () and Toshiyuki Yoneda
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Michiko Yoshida: Osaka 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

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7653

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