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.
Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan.
Nat Commun. 2015 Mar 26;6:6653. doi: 10.1038/ncomms7653.
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.
印度刺猬（Ihh）通过激活转录中介Gli2 以甲状旁腺激素相关蛋白（PTHrP）依赖和非依赖的方式调节软骨内骨化。然而，这些过程背后的分子机制仍不清楚。在这里，我们通过体内微阵列分析，鉴定出叉头框 C1（Foxc1）是 Gli2 的转录伴侣。Foxc1 通过其与 Gli2 的物理和功能相互作用，刺激 Ihh 靶基因的表达，包括 PTHrP 和 Col10a1。相反，显性负 Foxc1 抑制 Ihh 靶基因的表达。在 Foxc1 功能丧失的自发性突变小鼠（Foxc1(ch/ch)）中，软骨内骨化延迟，Ihh 靶基因的表达受到抑制。此外，Axenfeld-Rieger 综合征中观察到的病理性 Foxc1 错义突变会损害 Gli2-Foxc1 相互作用以及 Ihh 功能。我们的研究结果表明，Foxc1 是软骨内骨化过程中 Ihh-Gli2 信号的重要转录伴侣，而 Foxc1-Gli2 相互作用的破坏会导致 Axenfeld-Rieger 综合征中观察到的骨骼异常。
