Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation
Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation
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DOI：
10.1073/pnas.1502301112
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发表时间：
2015-04-14
影响因子：
11.1
通讯作者：
Long, Fanxin
中科院分区：
文献类型：
--
作者：
Shi, Yu;Chen, Jianquan;Long, Fanxin
Hedgehog (Hh) 信号对于胚胎发生过程中软骨内骨骼中的成骨细胞分化至关重要。然而，Hh 成骨细胞作用的分子机制尚不完全清楚。在这里，我们报告 Hh 显着诱导胰岛素样生长因子 2 (Igf2) 的表达，从而在成骨细胞分化过程中激活 mTORC2-Akt 信号级联。 Igf2-Akt 信号转而通过丝氨酸 230 稳定全长 Gli2，从而增强 Hh 转录激活的输出。重要的是，Hh 反应细胞中 Igf 信号受体 Igf1r 的基因缺失会减少小鼠胚胎中的骨形成。因此，Hh 通过正反馈机制参与 Igf 信号传导，从而激活成骨程序。
Hedgehog (Hh) signaling is essential for osteoblast differentiation in the endochondral skeleton during embryogenesis. However, the molecular mechanism underlying the osteoblastogenic role of Hh is not completely understood. Here, we report that Hh markedly induces the expression of insulin-like growth factor 2 (Igf2) that activates the mTORC2-Akt signaling cascade during osteoblast differentiation. Igf2-Akt signaling, in turn, stabilizes full-length Gli2 through Serine 230, thus enhancing the output of transcriptional activation by Hh. Importantly, genetic deletion of the Igf signaling receptor Igf1r specifically in Hh-responding cells diminishes bone formation in the mouse embryo. Thus, Hh engages Igf signaling in a positive feedback mechanism to activate the osteogenic program.