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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).
J Biol Chem 2012; 287(25):21429-38JB

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+Show Affiliations

Department of Orthodontics, Institute of Dentistry, University of Helsinki, Helsinki 00014, Finland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22547067

Citation

Tanimoto, Yukiho, et al. "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)." The Journal of Biological Chemistry, vol. 287, no. 25, 2012, pp. 21429-38.
Tanimoto Y, Veistinen L, Alakurtti K, et al. 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). J Biol Chem. 2012;287(25):21429-38.
Tanimoto, Y., Veistinen, L., Alakurtti, K., Takatalo, M., & Rice, D. P. (2012). 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). The Journal of Biological Chemistry, 287(25), pp. 21429-38. doi:10.1074/jbc.M112.362145.
Tanimoto Y, et al. 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). J Biol Chem. 2012 Jun 15;287(25):21429-38. PubMed PMID: 22547067.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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). AU - Tanimoto,Yukiho, AU - Veistinen,Lotta, AU - Alakurtti,Kirsi, AU - Takatalo,Maarit, AU - Rice,David P C, Y1 - 2012/04/30/ PY - 2012/5/2/entrez PY - 2012/5/2/pubmed PY - 2012/8/25/medline SP - 21429 EP - 38 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 287 IS - 25 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/22547067/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__ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=22547067 DB - PRIME DP - Unbound Medicine ER -