Tags

Type your tag names separated by a space and hit enter

Suppressor of Fused restraint of Hedgehog activity level is critical for osteogenic proliferation and differentiation during calvarial bone development.
J Biol Chem 2017; 292(38):15814-15825JB

Abstract

Hedgehog signaling plays crucial roles in the development of calvarial bone, relying on the activation of Gli transcription factors. However, the molecular mechanism of the role of regulated Gli protein level in osteogenic specification of mesenchyme still remains elusive. Here, we show by conditionally inactivating Suppressor of Fused (Sufu), a critical repressor of Hedgehog signaling, in Wnt1-Cre-mediated cranial neural crest (CNC) or Dermo1-Cre-mediated mesodermal lineages that Sufu restraint of Hedgehog activity level is critical for differentiation of preosteogenic mesenchyme. Ablation of Sufu results in failure of calvarial bone formation, including CNC-derived bones and mesoderm-derived bones, depending on the Cre line being used. Although mesenchymal cells populate to frontonasal destinations, where they are then condensed, Sufu deletion significantly inhibits the proliferation of osteoprogenitor cells, and these cells no longer differentiate into osteoblasts. We show that there is suppression of Runx2 and Osterix, the osteogenic regulators, in calvarial mesenchyme in the Sufu mutant. We show that down-regulation of several genes upstream to Runx2 and Osterix is manifested within the calvarial primordia, including Bmp2 and its downstream genes Msx1/2 and Dlx5 By contrast, we find that Gli1, the Hedgehog activity readout gene, is excessively activated in mesenchyme. Deletion of Sufu in CNC leads to a discernible decrease in the repressive Gli3 form and an increase in the full-length Gli2. Finally, we demonstrate that simultaneous deletion of Gli2 and Sufu in CNC completely restores calvarial bone formation, suggesting that a sustained level of Hedgehog activity is critical in specification of the osteogenic mesenchymal cells.

Authors+Show Affiliations

From the Zhejiang Key Laboratory for Organogenesis and Regenerative Technology, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China and.From the Zhejiang Key Laboratory for Organogenesis and Regenerative Technology, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China and.From the Zhejiang Key Laboratory for Organogenesis and Regenerative Technology, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China and.From the Zhejiang Key Laboratory for Organogenesis and Regenerative Technology, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China and.From the Zhejiang Key Laboratory for Organogenesis and Regenerative Technology, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China and.From the Zhejiang Key Laboratory for Organogenesis and Regenerative Technology, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China and.From the Zhejiang Key Laboratory for Organogenesis and Regenerative Technology, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China and.From the Zhejiang Key Laboratory for Organogenesis and Regenerative Technology, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China and.the Department of Ophthamology, Tulane Medical Center, Tulane University, New Orleans, Louisiana 70112.From the Zhejiang Key Laboratory for Organogenesis and Regenerative Technology, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China and zunyi_zhang@idrbio.org.

Pub Type(s)

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

Language

eng

PubMed ID

28794157

Citation

Li, Jianying, et al. "Suppressor of Fused Restraint of Hedgehog Activity Level Is Critical for Osteogenic Proliferation and Differentiation During Calvarial Bone Development." The Journal of Biological Chemistry, vol. 292, no. 38, 2017, pp. 15814-15825.
Li J, Cui Y, Xu J, et al. Suppressor of Fused restraint of Hedgehog activity level is critical for osteogenic proliferation and differentiation during calvarial bone development. J Biol Chem. 2017;292(38):15814-15825.
Li, J., Cui, Y., Xu, J., Wang, Q., Yang, X., Li, Y., ... Zhang, Z. (2017). Suppressor of Fused restraint of Hedgehog activity level is critical for osteogenic proliferation and differentiation during calvarial bone development. The Journal of Biological Chemistry, 292(38), pp. 15814-15825. doi:10.1074/jbc.M117.777532.
Li J, et al. Suppressor of Fused Restraint of Hedgehog Activity Level Is Critical for Osteogenic Proliferation and Differentiation During Calvarial Bone Development. J Biol Chem. 2017 09 22;292(38):15814-15825. PubMed PMID: 28794157.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppressor of Fused restraint of Hedgehog activity level is critical for osteogenic proliferation and differentiation during calvarial bone development. AU - Li,Jianying, AU - Cui,Ying, AU - Xu,Jie, AU - Wang,Qihui, AU - Yang,Xueqin, AU - Li,Yan, AU - Zhang,Xiaoyun, AU - Qiu,Mengsheng, AU - Zhang,Ze, AU - Zhang,Zunyi, Y1 - 2017/08/09/ PY - 2017/01/22/received PY - 2017/07/04/revised PY - 2017/8/11/pubmed PY - 2017/10/11/medline PY - 2017/8/11/entrez KW - Gli2/3 KW - Hedgehog signaling pathway KW - Sufu KW - craniofacial development KW - gene knockout KW - intramembranous ossification KW - mouse KW - neural crest-derived mesenchyme KW - osteoblast KW - skull vault SP - 15814 EP - 15825 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 292 IS - 38 N2 - Hedgehog signaling plays crucial roles in the development of calvarial bone, relying on the activation of Gli transcription factors. However, the molecular mechanism of the role of regulated Gli protein level in osteogenic specification of mesenchyme still remains elusive. Here, we show by conditionally inactivating Suppressor of Fused (Sufu), a critical repressor of Hedgehog signaling, in Wnt1-Cre-mediated cranial neural crest (CNC) or Dermo1-Cre-mediated mesodermal lineages that Sufu restraint of Hedgehog activity level is critical for differentiation of preosteogenic mesenchyme. Ablation of Sufu results in failure of calvarial bone formation, including CNC-derived bones and mesoderm-derived bones, depending on the Cre line being used. Although mesenchymal cells populate to frontonasal destinations, where they are then condensed, Sufu deletion significantly inhibits the proliferation of osteoprogenitor cells, and these cells no longer differentiate into osteoblasts. We show that there is suppression of Runx2 and Osterix, the osteogenic regulators, in calvarial mesenchyme in the Sufu mutant. We show that down-regulation of several genes upstream to Runx2 and Osterix is manifested within the calvarial primordia, including Bmp2 and its downstream genes Msx1/2 and Dlx5 By contrast, we find that Gli1, the Hedgehog activity readout gene, is excessively activated in mesenchyme. Deletion of Sufu in CNC leads to a discernible decrease in the repressive Gli3 form and an increase in the full-length Gli2. Finally, we demonstrate that simultaneous deletion of Gli2 and Sufu in CNC completely restores calvarial bone formation, suggesting that a sustained level of Hedgehog activity is critical in specification of the osteogenic mesenchymal cells. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/28794157/Suppressor_of_Fused_restraint_of_Hedgehog_activity_level_is_critical_for_osteogenic_proliferation_and_differentiation_during_calvarial_bone_development_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=28794157 DB - PRIME DP - Unbound Medicine ER -