Shi Yu, Chen Jianquan, Karner Courtney M, Long Fanxin
Departments of Orthopaedic Surgery.
Departments of Orthopaedic Surgery, Medicine, and Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110
Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):4678-83. doi: 10.1073/pnas.1502301112. Epub 2015 Mar 30.
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.
刺猬(Hh)信号通路对于胚胎发育过程中软骨内骨的成骨细胞分化至关重要。然而,Hh在成骨细胞生成中的作用的分子机制尚未完全阐明。在此,我们报告Hh显著诱导胰岛素样生长因子2(Igf2)的表达,Igf2在成骨细胞分化过程中激活mTORC2-Akt信号级联反应。反过来,Igf2-Akt信号通路通过丝氨酸230稳定全长Gli2,从而增强Hh转录激活的输出。重要的是,在Hh反应性细胞中特异性缺失Igf信号受体Igf1r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信号通路以激活成骨程序。