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J. Biol. Chem., Vol. 281, Issue 27, 18363-18369, July 7, 2006

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Functional Consequences of Interactions between Pax9 and Msx1 Genes in Normal and Abnormal Tooth Development^*

Takuya Ogawa, Hitesh Kapadia, Jian Q. Feng^¶, Rajendra Raghow^||1, Heiko Peters^**, and Rena N. D'Souza²

From the Department of Orthodontics, University of Texas Health Science Center at Houston-Dental Branch, Houston, Texas 77030, the Program in Genes and Development, Graduate School of Biomedical Sciences (GSBS), University of Texas Health Science Center and M.D. Anderson Cancer Center, Houston, Texas 77030, the ^¶Department of Oral Biology, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri 64108, the ^||Department of Pharmacology, University of Tennessee Health Science Center and Department of Veterans Affairs Medical Center, Memphis, Tennessee 38104, the ^**Institute of Human Genetics, University of Newcastle, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, United Kingdom, and the Department of Biomedical Sciences, Baylor College of Dentistry, Dallas, Texas 75246

Pax9 and Msx1 encode transcription factors that are known to be essential for the switch in odontogenic potential from the epithelium to the mesenchyme. Multiple lines of evidence suggest that these molecules play an important role in the maintenance of mesenchymal Bmp4 expression, which ultimately drives morphogenesis of the dental organ. Here we demonstrate that Pax9 is able to directly regulate Msx1 expression and interact with Msx1 at the protein level to enhance its ability to transactivate Msx1 and Bmp4 expression during tooth development. In addition, we tested how a missense mutation (T62C) in the paired domain of PAX9 that is responsible for human tooth agenesis (1) affects its functions. Our data indicate that although the mutant Pax9 protein (L21P) can bind to the Msx1 protein, it fails to transactivate the Msx1 and Bmp4 promoter, presumably because of its inability to bind cognate paired domain recognition sequences. In addition, synergistic transcriptional activation of the Bmp4 promoter was lost with coexpression of mutant Pax9 and wild-type Msx1. This suggests that Pax9 is critical for the regulation of Bmp4 expression through its paired domain rather than Msx1. Our findings demonstrate the partnership of Pax9 and Msx1 in a signaling pathway that involves Bmp4. Furthermore, the regulation of Bmp4 expression by the interaction of Pax9 with Msx1 at the level of transcription and through formation of a protein complex determines the fate of the transition from bud to cap stage during tooth development.

Received for publication, February 17, 2006

^* This work was supported by National Institutes of Health Grants R01 DE13668 (to R. N. D.), K08 DE14237 (to H. K.), and DE 16346 (to T. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Senior Research Career Scientist of the Department of Veterans Affairs.

² To whom correspondence should be addressed: Dept. of Biomedical Sciences, Baylor College of Dentistry, 3302 Gaston Ave, Dallas, TX 75246. Tel.: 214-828-8260; Fax: 214-828-8951; E-mail: rdsouza{at}bcd.tamhsc.edu.

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