Abstract
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.
Highlights
Runx2 and Axin2 are required for proper skeletal development
Runx2 Regulates Axin2 Expression in Osteoblasts—To understand the genetic interplay between Axin2 and Runx2, we examined Axin2 transcripts using mRNA isolated from calvarial cells of Runx2Ϫ/Ϫ E17.5 embryos [40]
Both Runx2Ϫ/Ϫ and Hdac3 CKOOsx calvarial osteoblasts express more Axin2 than WT cells, which may be explained by a loss of the repressive effects of Runx2 and Hdac3 on Axin2 transcription
Summary
Runx and Axin are required for proper skeletal development. Results: Runx and Hdac repress Axin transcription in osteoblasts. These double mutant mice had longer skulls than Axin2؊/؊ mice, indicating that Runx 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 Axin to prevent the untimely closure of the calvarial sutures. To determine whether Axin, Runx, and Hdac directly interact and are components of the same molecular pathway that regulates suture closure, we performed molecular experiments and crossed the Axin2Ϫ/Ϫ and Runx2ϩ/Ϫ mouse models to generate double mutant Axin2Ϫ/Ϫ:Runx2ϩ/Ϫ mice These studies demonstrate that Runx haploinsufficiency rescues the craniosynostosis phenotype in Axin2Ϫ/Ϫ mice and that Runx directly represses Axin expression in an Hdac3-dependent manner
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