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 (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. Skeletal development relies on endochondral ossification. Here the authors show that transcription factors Foxc1 and Gli2 interact to modulate expression of Ihh target genes that control endochondral ossification, and that disruption of this interaction partly underlies skeletal disorders in the Axenfeld–Rieger syndrome.