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Sci. Signal., 10 January 2012
Vol. 5, Issue 206, p. ra4
[DOI: 10.1126/scisignal.2002414]


A Wnt-Bmp Feedback Circuit Controls Intertissue Signaling Dynamics in Tooth Organogenesis

Daniel J. O’Connell1*, Joshua W. K. Ho1,2*, Tadanori Mammoto3, Annick Turbe-Doan1, Joyce T. O’Connell4, Psalm S. Haseley1,2, Samuel Koo1,5, Nobuhiro Kamiya6, Donald E. Ingber3,7,8, Peter J. Park1,2,9, and Richard L. Maas1{dagger}

1 Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
2 Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
3 Vascular Biology Program, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
4 Division of Matrix Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
5 Division of Periodontology, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
6 Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
7 Wyss Institute for Biologically Inspired Engineering at Harvard University, Wyss Institute, Boston, MA 02115, USA.
8 Department of Engineering and Applied Sciences, Harvard School of Engineering and Applied Sciences, Cambridge, MA 02139, USA.
9 Informatics Program, Children’s Hospital Boston, Boston, MA 02115, USA.

* These authors contributed equally to this work.

Abstract: Many vertebrate organs form through the sequential and reciprocal exchange of signaling molecules between juxtaposed epithelial and mesenchymal tissues. We undertook a systems biology approach that combined the generation and analysis of large-scale spatiotemporal gene expression data with mouse genetic experiments to gain insight into the mechanisms that control epithelial-mesenchymal signaling interactions in the developing mouse molar tooth. We showed that the shift in instructive signaling potential from dental epithelium to dental mesenchyme was accompanied by temporally coordinated genome-wide changes in gene expression in both compartments. To identify the mechanism responsible, we developed a probabilistic technique that integrates regulatory evidence from gene expression data and from the literature to reconstruct a gene regulatory network for the epithelial and mesenchymal compartments in early tooth development. By integrating these epithelial and mesenchymal gene regulatory networks through the action of diffusible extracellular signaling molecules, we identified a key epithelial-mesenchymal intertissue Wnt-Bmp (bone morphogenetic protein) feedback circuit. We then validated this circuit in vivo with compound genetic mutations in mice that disrupted this circuit. Moreover, mathematical modeling demonstrated that the structure of the circuit accounted for the observed reciprocal signaling dynamics. Thus, we have identified a critical signaling circuit that controls the coordinated genome-wide expression changes and reciprocal signaling molecule dynamics that occur in interacting epithelial and mesenchymal compartments during organogenesis.

{dagger} To whom correspondence should be addressed. E-mail: maas{at}

Citation: D. J. O’Connell, J. W. K. Ho, T. Mammoto, A. Turbe-Doan, J. T. O’Connell, P. S. Haseley, S. Koo, N. Kamiya, D. E. Ingber, P. J. Park, R. L. Maas, A Wnt-Bmp Feedback Circuit Controls Intertissue Signaling Dynamics in Tooth Organogenesis. Sci. Signal. 5, ra4 (2012).

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