Nathan Smith and Yufeng Dong contributed equally to this work.
Overlapping expression of Runx1(Cbfa2) and Runx2(Cbfa1) transcription factors supports cooperative induction of skeletal development†
Article first published online: 13 SEP 2004
Copyright © 2004 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 203, Issue 1, pages 133–143, April 2005
How to Cite
Smith, N., Dong, Y., Lian, J. B., Pratap, J., Kingsley, P. D., van Wijnen, A. J., Stein, J. L., Schwarz, E. M., O'Keefe, R. J., Stein, G. S. and Drissi, M. H. (2005), Overlapping expression of Runx1(Cbfa2) and Runx2(Cbfa1) transcription factors supports cooperative induction of skeletal development. J. Cell. Physiol., 203: 133–143. doi: 10.1002/jcp.20210
- Issue published online: 25 JAN 2005
- Article first published online: 13 SEP 2004
- Manuscript Accepted: 20 JUL 2004
- Manuscript Received: 2 JUN 2004
Identifying the genetic pathways that regulate skeletal development is necessary to correct a variety of cartilage and bone abnormalities. The Runx family of transcription factors play a fundamental role in organ development and cell differentiation. Initial studies have shown that both Runx1 and Runx2 are expressed in pre-chondrogenic mesenchyme of the developing embryo at E12.5. Abrogation of the Runx2 gene completely inhibits bone formation yet the cartilage anlagen in these mice is fully formed. In the present study, we hypothesized that Runx1 may compensate for the lack of Runx2 in vivo to induce the early stages of skeletal formation and development. Histologic β-gal stained sections using the Runx1+/−-Lac-Z mice demonstrate Runx1 promoter activity in pre-chondrocytic cell populations. In situ hybridization using Runx1 and Runx2 specific probes indicate that both factors are expressed in mesenchymal stem cell progenitors during early embryonic development. During later stages of mouse skeletal formation, Runx1 is excluded from the hypertrophic cartilage while Runx2 is present in these matured chondrocyte populations. Quantification of Runx expression by real time RT-PCR and Western blot analyses reveals that Runx1 and Runx2 are differentially modulated during embryogenesis suggesting a temporal role for each of these transcriptional regulators during skeletal formation. We provide evidence that haploinsufficiency results in normal appearing embryo skeletons of heterozygote Runx2 and Runx1 mutant mouse models; however, a delay in bone formation was identified in the calvarium. In summary, our results support a function for Runx1 and Runx2 during skeletal development with a possible role for Runx1 in mediating early events of endochondral and intramembranous bone formation, while Runx2 is a potent inducer of late stages of chondrocyte and osteoblast differentiation. © 2004 Wiley-Liss, Inc.