Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Significance Hedgehog (Hh) signaling is essential for embryonic bone formation in mammals. However, how Hh signaling executes the osteogenic function is not clear. We describe a positive feedback mechanism whereby Hh-Gli2 signaling induces expression of insulin-like growth factor 2 (Igf2), which signals via protein kinases mTORC2 and Akt to stabilize Gli2 and potentiate Hh induction of osteoblast differentiation. The Hh-Igf positive feedback loop may have general implications for Hh signaling in development and disease. 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.