Tooth development has long been used as a powerful model system for studying the molecular mechanisms regulating organogenesis and the pathogenic mechanisms of tooth developmental anomalies in humans. A critical step in tooth development is the activation of odontogenic potential in the neural crest-derived tooth mesenchyme, which is responsible for driving tooth morphogenesis from the tooth bud stage and is sufficient to induce tooth organogenesis when recombined with non-dental epithelium. Failure to activate mesenchymal odontogenic potential is associated with tooth bud developmental arrest, as seen in mice lacking the Msx1 transcription factor. Mutations in MSX1 are also associated with tooth agenesis in humans. Previous studies suggested that Bmp4 is an important odontogenic signal downstream of Msx1. Bmp4 mRNA expression was downregulated in Msx1-/- tooth mesenchyme. However, we found that mice with neural crest specific inactivation of the Bmp4 gene exhibit developmental arrest of only the mandibular molar buds but their maxillary molars and incisors developed to mineralized teeth. We carried out RNAseq analyses of microdissected tooth bud mesenchyme and found that the mandibular molar mesenchyme expresses much higher levels of secreted Wnt antagonists than does the maxillary molar mesenchyme. We found that tissue- specific inactivation of ?-catenin, the obligatory transducer of canonical Wnt signaling, in the early tooth mesenchyme caused tooth bud developmental arrest, suggesting that the higher levels of Wnt antagonists in mandibular molar tooth mesenchyme contribute to the dramatic differences in maxillary and mandibular molar tooth defects in the Bmp4 mutant mice. Moreover, we discovered recently that inactivation of the Osr2 transcription factor caused supernumerary tooth formation from oral epithelium lingual to the molar tooth germs in mice. Osr2 is expressed in a gradient pattern and suppressed the domain of mesenchymal odontogenic potential along the buccolingual axis of the developing tooth mesenchyme. Whereas Msx1-/- mutant mice had tooth development arrested at the bud stage, Msx1-/-Osr2-/- double mutants exhibited nearly normal first molar morphogenesis but did not initiate supernumerary tooth development. Moreover, we found that Msx1 and Osr2 regulate antagonistically the expression of secreted Wnt antagonists in the developing tooth mesenchyme. Together, these data suggest novel mechanisms involving Bmp, Msx1, Osr2, and Wnt signaling pathways in the regulation of mesenchymal odontogenic potential. The major aims of this project are to identify, characterize, and integrate the molecula mechanisms combining these factors and pathways regulating early odontogenesis, using multifaceted experimental approaches, including in vivo pharmacological rescue, nanogram scale RNAseq-based gene expression profiling, and combined explant organ culture and genetic functional assays. Data from this project will significantly improve the current understanding of the molecular mechanisms of tooth development and multiple human birth defects and will facilitate development of new therapeutic strategies.

Public Health Relevance

Mutations in the MSX1 and WNT10A genes cause congenital tooth agenesis. Mutations in MSX1 and other WNT genes cause other major birth defects as well, such as cleft lip and palate. This project uses the developing tooth as a model system to identify, characterize, and integrate the molecular mechanisms involving MSX1 and WNT signaling pathway in the regulation of organ development. Findings in this project will lead to significant improvement in understanding of the developmental mechanisms and development of new therapies for major birth defects.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Scholnick, Steven
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Kwon, H-J E; Jia, S; Lan, Y et al. (2017) Activin and Bmp4 Signaling Converge on Wnt Activation during Odontogenesis. J Dent Res 96:1145-1152
Li, C; Lan, Y; Krumlauf, R et al. (2017) Modulating Wnt Signaling Rescues Palate Morphogenesis in Pax9 Mutant Mice. J Dent Res 96:1273-1281
Fu, X; Xu, J; Chaturvedi, P et al. (2017) Identification of Osr2 Transcriptional Target Genes in Palate Development. J Dent Res 96:1451-1458
Xu, Jingyue; Liu, Han; Lan, Yu et al. (2016) A Shh-Foxf-Fgf18-Shh Molecular Circuit Regulating Palate Development. PLoS Genet 12:e1005769
Jia, Shihai; Kwon, Hyuk-Jae Edward; Lan, Yu et al. (2016) Bmp4-Msx1 signaling and Osr2 control tooth organogenesis through antagonistic regulation of secreted Wnt antagonists. Dev Biol 420:110-119
Kwon, H J E; Park, E K; Jia, S et al. (2015) Deletion of Osr2 Partially Rescues Tooth Development in Runx2 Mutant Mice. J Dent Res 94:1113-9
Lan, Yu; Jia, Shihai; Jiang, Rulang (2014) Molecular patterning of the mammalian dentition. Semin Cell Dev Biol 25-26:61-70
Jia, Shihai; Zhou, Jing; Gao, Yang et al. (2013) Roles of Bmp4 during tooth morphogenesis and sequential tooth formation. Development 140:423-32
Zhou, Jing; Gao, Yang; Lan, Yu et al. (2013) Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis. Development 140:4709-18
Zhou, Jing; Gao, Yang; Zhang, Zunyi et al. (2011) Osr2 acts downstream of Pax9 and interacts with both Msx1 and Pax9 to pattern the tooth developmental field. Dev Biol 353:344-53

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