Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2

Noriko Funato, Shelby L. Chapman, Marc D. Mckee, Hiromasa Funato, Jesse A. Morris, John M. Shelton, James A. Richardson, Hiromi Yanagisawa

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Members of the basic helix-loop-helix (bHLH) family of transcription factors regulate the specification and differentiation of numerous cell types during embryonic development. Hand1 and Hand2 are expressed by a subset of neural crest cells in the anterior branchial arches and are involved in craniofacial development. However, the precise mechanisms by which Hand proteins mediate biological actions and regulate downstream target genes in branchial arches is largely unknown. Here, we report that Hand2 negatively regulates intramembranous ossification of the mandible by directly inhibiting the transcription factor Runx2, a master regulator of osteoblast differentiation. Hand proteins physically interact with Runx2, suppressing its DNA binding and transcriptional activity. This interaction is mediated by the N-terminal domain of the Hand protein and requires neither dimerization with other bHLH proteins nor DNA binding. We observed partial colocalization of Hand2 and Runx2 in the mandibular primordium of the branchial arch, and downregulation of Hand2 precedes Runx2-driven osteoblast differentiation. Hand2 hypomorphic mutant mice display insufficient mineralization and ectopic bone formation in the mandible due to accelerated osteoblast differentiation, which is associated with the upregulation and ectopic expression of Runx2 in the mandibular arch. Here, we show that Hand2 acts as a novel inhibitor of the Runx2-DNA interaction and thereby regulates osteoblast differentiation in branchial arch development.

Original languageEnglish (US)
Pages (from-to)615-625
Number of pages11
JournalDevelopment
Volume136
Issue number4
DOIs
StatePublished - Feb 15 2009

Fingerprint

Branchial Region
Osteoblasts
Hand
DNA
Mandible
Osteogenesis
Basic Helix-Loop-Helix Transcription Factors
Neural Crest
DNA-Binding Proteins
Dimerization
Embryonic Development
Cell Differentiation
Proteins
Transcription Factors
Up-Regulation
Down-Regulation
Genes

Keywords

  • Branchial arch
  • Craniofacial
  • Intramembranous ossification
  • Mandible
  • Mouse
  • Neural crest
  • Osteoblast

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

Cite this

Funato, N., Chapman, S. L., Mckee, M. D., Funato, H., Morris, J. A., Shelton, J. M., ... Yanagisawa, H. (2009). Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2. Development, 136(4), 615-625. https://doi.org/10.1242/dev.029355

Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2. / Funato, Noriko; Chapman, Shelby L.; Mckee, Marc D.; Funato, Hiromasa; Morris, Jesse A.; Shelton, John M.; Richardson, James A.; Yanagisawa, Hiromi.

In: Development, Vol. 136, No. 4, 15.02.2009, p. 615-625.

Research output: Contribution to journalArticle

Funato, N, Chapman, SL, Mckee, MD, Funato, H, Morris, JA, Shelton, JM, Richardson, JA & Yanagisawa, H 2009, 'Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2', Development, vol. 136, no. 4, pp. 615-625. https://doi.org/10.1242/dev.029355
Funato N, Chapman SL, Mckee MD, Funato H, Morris JA, Shelton JM et al. Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2. Development. 2009 Feb 15;136(4):615-625. https://doi.org/10.1242/dev.029355
Funato, Noriko ; Chapman, Shelby L. ; Mckee, Marc D. ; Funato, Hiromasa ; Morris, Jesse A. ; Shelton, John M. ; Richardson, James A. ; Yanagisawa, Hiromi. / Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2. In: Development. 2009 ; Vol. 136, No. 4. pp. 615-625.
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