A twist code determines the onset of osteoblast differentiation

Peter Bialek, Britt Kern, Xiangli Yang, Marijke Schrock, Drazen Sosic, Nancy Hong, Hua Wu, Kai Yu, David M. Ornitz, Eric N. Olson, Monica J. Justice, Gerard Karsenty

Research output: Contribution to journalArticlepeer-review

485 Scopus citations

Abstract

Runx2 is necessary and sufficient for osteoblast differentiation, yet its expression precedes the appearance of osteoblasts by 4 days. Here we show that Twist proteins transiently inhibit Runx2 function during skeletogenesis. Twist-1 and -2 are expressed in Runx2 -expressing cells throughout the skeleton early during development, and osteoblast-specific gene expression occurs only after their expression decreases. Double heterozygotes for Twist-1 and Runx2 deletion have none of the skull abnormalities observed in Runx2+/- mice, a Twist-2 null background rescues the clavicle phenotype of Runx2+/- mice, and Twist-1 or -2 deficiency leads to premature osteoblast differentiation. Furthermore, Twist-1 overexpression inhibits osteoblast differentiation without affecting Runx2 expression. Twist proteins' antiosteogenic function is mediated by a novel domain, the Twist box, which interacts with the Runx2 DNA binding domain to inhibit its function. In vivo mutagenesis confirms the antiosteogenic function of the Twist box. Thus, relief of inhibition by Twist proteins is a mandatory event precluding osteoblast differentiation.

Original languageEnglish (US)
Pages (from-to)423-435
Number of pages13
JournalDevelopmental cell
Volume6
Issue number3
DOIs
StatePublished - Mar 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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