Regulation of the activity of the transcription factor Runx2 by two homeobox proteins, Msx2 and Dlx5

Background: Runx2, formerly called PEBP2 alphaA or Cbfa1, is a transcriptio n factor whose deletion causes a complete lack of ossification. It directly regulates the expression of osteoblast-specific genes through the osteobla st-specific cis-acting element found in the promoter region of these genes. Results: In this study, we have found conditions in which induction of the expression of Runx2 is not accompanied by expression of an osteoblast-speci fic gene, osteocalcin in C2C12 cells. This finding suggests the existence o f a repressor of the activity of Runx2. We have then found that the homeobo x protein Msx2 is able to repress the transcription activity of Runx2 by in teracting with it. Furthermore, our results have shown that the other homeo box protein D1x5 has an activity which interferes with both abilities of Ms x2 to interact with Runx2 and repress its transcription activity. It has pr eviously been shown that a missense mutation of Msx2 (P148H) causes Boston- type craniosynostosis in humans. Interestingly, while this mutant form of M sx2 was able to bind to Runx2 and repress its activity, these abilities of Msx2 (P148H) were not subject to regulation by D1x5. Conclusion: These results suggest that regulation of the activity of Runx2 by Msx2 and D1x5 plays an important role in the mammalian skull development .