title: Prevention of premature fusion of calvarial suture in GLI-Kruppel family member 3 (Gli3)-deficient mice by removing one allele of Runt-related transcription factor 2 (Runx2).
abstract: Mutations in the gene encoding the zinc finger transcription factor GLI3 (GLI-Kruppel family member 3) have been identified in patients with Grieg cephalopolysyndactyly syndrome in which premature fusion of calvarial suture (craniosynostosis) is an infrequent but important feature. Here, we show that Gli3 acts as a repressor in the developing murine calvaria and that Dlx5, Runx2 type II isoform (Runx2-II), and Bmp2 are expressed ectopically in the calvarial mesenchyme, which results in aberrant osteoblastic differentiation in Gli3-deficient mouse (Gli3(Xt-J/Xt-J)) and resulted in craniosynostosis. At the same time, enhanced activation of phospho-Smad1/5/8 (pSmad1/5/8), which is a downstream mediator of canonical Bmp signaling, was observed in Gli3(Xt-J/Xt-J) embryonic calvaria. Therefore, we generated Gli3;Runx2 compound mutant mice to study the effects of decreasing Runx2 dosage in a Gli3(Xt-J/Xt-J) background. Gli3(Xt-J/Xt-J) Runx2(+/-) mice have neither craniosynostosis nor additional ossification centers in interfrontal suture and displayed a normalization of Dlx5, Runx2-II, and pSmad1/5/8 expression as well as sutural mesenchymal cell proliferation. These findings suggest a novel role for Gli3 in regulating calvarial suture development by controlling canonical Bmp-Smad signaling, which integrates a Dlx5/Runx2-II cascade. We propose that targeting Runx2 might provide an attractive way of preventing craniosynostosis in patients.
authors.affiliation: Department of Orthodontics, Institute of Dentistry, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Yukiho
authors.initials: Y
authors.lastname: Tanimoto
authors.forename: Lotta
authors.initials: L
authors.lastname: Veistinen
authors.forename: Kirsi
authors.initials: K
authors.lastname: Alakurtti
authors.forename: Maarit
authors.initials: M
authors.lastname: Takatalo
authors.forename: David P C
authors.initials: DP
authors.lastname: Rice
mesh_terms: D000168:Acrocephalosyndactylia / Q000196:embryology* / Q000235:genetics / Q000517:prevention & control; D000818:Animals; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000196:embryology; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000196:embryology*; D051785:Smad Proteins; D000074290:Zinc Finger Protein Gli3
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C501120:Dlx5 protein, mouse; C465571:Gli3 protein, mouse; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C493716:Runx2 protein, mouse; D051785:Smad Proteins; D000074290:Zinc Finger Protein Gli3; D053505:Matrix Metalloproteinases, Secreted