title: Runx2 protein represses Axin2 expression in osteoblasts and is required for craniosynostosis in Axin2-deficient mice.
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.
authors.affiliation: Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: McGee-Lawrence
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Krista L
authors.initials: KL
authors.lastname: Bledsoe
authors.forename: Hai
authors.initials: H
authors.lastname: Wu
authors.forename: John R
authors.initials: JR
authors.lastname: Hawse
authors.forename: Malayannan
authors.initials: M
authors.lastname: Subramaniam
authors.forename: David F
authors.initials: DF
authors.lastname: Razidlo
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Stensgard
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Wei
authors.initials: W
authors.lastname: Hsu
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
mesh_terms: D016475:3T3 Cells; D000818:Animals; D060466:Axin Protein / Q000235:genetics* / Q000502:physiology*; D001854:Bone Marrow Cells; D001842:Bone and Bones / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D003398:Craniosynostoses / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D012886:Skull / Q000473:pathology; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D060466:Axin Protein; D050659:Core Binding Factor Alpha 1 Subunit; D006655:Histone Deacetylases; D051153:Wnt Proteins; D000099186:Histone Deacetylase 3; C111729:Axin2 protein, mouse; C493716:Runx2 protein, mouse