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.
Keywords: Akt; Gli2; Hedgehog; Igf; osteoblast.
Publication types
- Research Support, N.I.H., Extramural
MeSH terms
- Animals
- Blotting, Western
- Cell Differentiation*
- Cell Line
- Feedback, Physiological / drug effects
- Female
- Hedgehog Proteins / agonists
- Hedgehog Proteins / genetics
- Hedgehog Proteins / metabolism*
- In Situ Hybridization
- Insulin-Like Growth Factor II / genetics
- Insulin-Like Growth Factor II / metabolism*
- Kruppel-Like Transcription Factors / genetics
- Kruppel-Like Transcription Factors / metabolism
- Mechanistic Target of Rapamycin Complex 2
- Mesenchymal Stem Cells / drug effects
- Mesenchymal Stem Cells / metabolism
- Mice, Knockout
- Mice, Transgenic
- Morpholines / pharmacology
- Multiprotein Complexes / genetics
- Multiprotein Complexes / metabolism
- Osteoblasts / cytology
- Osteoblasts / metabolism*
- Proto-Oncogene Proteins c-akt / genetics
- Proto-Oncogene Proteins c-akt / metabolism
- Purines / pharmacology
- RNA Interference
- Receptors, Somatomedin / genetics
- Receptors, Somatomedin / metabolism
- Recombinant Proteins / pharmacology
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction / drug effects
- Signal Transduction / genetics
- TOR Serine-Threonine Kinases / genetics
- TOR Serine-Threonine Kinases / metabolism
- Zinc Finger Protein GLI1
Substances
- Gli1 protein, mouse
- Hedgehog Proteins
- IGF2 protein, mouse
- Kruppel-Like Transcription Factors
- Morpholines
- Multiprotein Complexes
- Purines
- Receptors, Somatomedin
- Recombinant Proteins
- Zinc Finger Protein GLI1
- Insulin-Like Growth Factor II
- Mechanistic Target of Rapamycin Complex 2
- Proto-Oncogene Proteins c-akt
- TOR Serine-Threonine Kinases
- purmorphamine