Runx2 Protein Represses Axin2 Expression in Osteoblasts and Is Required for Craniosynostosis in Axin2-deficient Mice

Runx2 and Axin2 regulate craniofacial development and skeletal maintenance. Runx2 is essential for calvarial bone development, as Runx2 haploinsufficiency causes cleidocranial dysplasia. In contrast, Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Axin2 levels are e...

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Veröffentlicht in:The Journal of biological chemistry 2013-02, Vol.288 (8), p.5291-5302
Hauptverfasser: McGee-Lawrence, Meghan E., Li, Xiaodong, Bledsoe, Krista L., Wu, Hai, Hawse, John R., Subramaniam, Malayannan, Razidlo, David F., Stensgard, Bridget A., Stein, Gary S., van Wijnen, Andre J., Lian, Jane B., Hsu, Wei, Westendorf, Jennifer J.
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Sprache:eng
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Zusammenfassung:Runx2 and Axin2 regulate craniofacial development and skeletal maintenance. Runx2 is essential for calvarial bone development, as Runx2 haploinsufficiency causes cleidocranial dysplasia. In contrast, Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Axin2 levels are elevated in Runx2−/− calvarial cells, and Runx2 represses transcription of Axin2 mRNA, suggesting a direct relationship between these factors in vivo. Here we demonstrate that Runx2 binds several regions of the Axin2 promoter and that Runx2-mediated repression of Axin2 transcription depends on Hdac3. To determine whether Runx2 contributes to the etiology of Axin2 deficiency-induced craniosynostosis, we generated Axin2−/−:Runx2+/− mice. These double mutant mice had longer skulls than Axin2−/− mice, indicating that Runx2 haploinsufficiency rescued the craniosynostosis phenotype of Axin2−/− mice. Together, these studies identify a key mechanistic pathway for regulating intramembranous bone development within the skull that involves Runx2- and Hdac3-mediated suppression of Axin2 to prevent the untimely closure of the calvarial sutures.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.414995