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)

• Published in: The Journal of biological chemistry Vol. 287; no. 25; pp. 21429 - 21438
• Main Authors: Tanimoto, Yukiho, Veistinen, Lotta, Alakurtti, Kirsi, Takatalo, Maarit, Rice, David P.C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.06.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Acrocephalosyndactylia - embryology; Acrocephalosyndactylia - genetics; Acrocephalosyndactylia - prevention & control; Animals; Bone; Bone Morphogenetic Protein (BMP); Cell Differentiation; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Craniosynostosis; Development; Developmental Biology; Differentiation; Gli3; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Matrix Metalloproteinases, Secreted - genetics; Matrix Metalloproteinases, Secreted - metabolism; Mesoderm - embryology; Mice; Mice, Mutant Strains; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Osteoblasts; Osteoblasts - metabolism; Runx2; Signal Transduction; Skull - embryology; Smad Proteins; Zinc Finger Protein Gli3; Bone Morphogenetic Protein (BMP); Craniosynostosis; Development; Bone; Differentiation; Osteoblasts; Gli3; Runx2
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.362145

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 (Gli3Xt-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 Gli3Xt-J/Xt-J embryonic calvaria. Therefore, we generated Gli3;Runx2 compound mutant mice to study the effects of decreasing Runx2 dosage in a Gli3Xt-J/Xt-J background. Gli3Xt-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. Gli3-deficient mice (Gli3Xt-J/Xt-J) show premature suture closure (craniosynostosis). Gli3Xt-J/Xt-J mice have aberrant cell proliferation and osteogenic differentiation in the sutures. Reducing the dosage of Runx2 (Gli3Xt-J/Xt-J;Runx2+/− mice) rescues the abnormality through canonical Bmp-Smad signaling. Gli3 represses bone formation Bmp-Smad signaling, which integrates Dlx5/Runx2-II cascade. Targeting Runx2 might provide an attractive way of preventing craniosynostosis in patients.