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

Yu Shi, Jianquan Chen, Courtney M. Karner, Fanxin Long

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4678-4683
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number15
DOIs
StatePublished - Apr 14 2015
Externally publishedYes

Keywords

  • Akt
  • Gli2
  • Hedgehog
  • Igf
  • Osteoblast

ASJC Scopus subject areas

  • General

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