title: Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation.
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.
authors.affiliation: Departments of Orthopaedic Surgery.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Departments of Orthopaedic Surgery.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Departments of Orthopaedic Surgery.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Karner
authors.affiliation: Departments of Orthopaedic Surgery, Medicine, and Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110 flong@wustl.edu.
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D053823:Hedgehog Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C513121:IGF2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009025:Morpholines; D046912:Multiprotein Complexes; D011687:Purines; D017451:Receptors, Somatomedin; D011994:Recombinant Proteins; D000071676:Zinc Finger Protein GLI1; D007335:Insulin-Like Growth Factor II; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C470893:purmorphamine
keywords: Akt; Gli2; Hedgehog; Igf; osteoblast
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