Mesenchymal Wnt/β-catenin signaling limits tooth number

Area of Science:

• Developmental biology
• Genetics
• Oral biology

Background:

• Tooth agenesis is a frequent human developmental anomaly affecting permanent dentition.
• Mutations in Wnt/β-catenin signaling pathways, particularly in the Wnt feedback inhibitor *AXIN2*, are linked to tooth agenesis.
• Understanding Wnt signaling's role in sequential tooth formation is crucial for addressing dental anomalies.

Purpose of the Study:

• To investigate the function of Wnt/β-catenin signaling during sequential molar tooth formation.
• To elucidate the roles of *AXIN2* and *Runx2* in regulating tooth development.
• To explore the molecular mechanisms underlying contrasting dental phenotypes associated with *AXIN2* and *RUNX2* mutations.

Main Methods:

• Utilized mouse models to study Wnt/β-catenin signaling during sequential tooth formation.
• Employed genetic and pharmacological activation of Wnt/β-catenin signaling in oral epithelium and dental mesenchyme.
• Analyzed gene expression patterns, including Wnt antagonists (*Axin2*, *Drapc1*), and downstream effectors like *Bmp4* and *Runx2*.

Main Results:

• Activation of epithelial Wnt/β-catenin signaling led to continuous tooth initiation, coupled with increased Wnt antagonists and reduced signaling in the mesenchyme.
• Activation of mesenchymal Wnt/β-catenin signaling inhibited sequential tooth formation, partly mediated by *Bmp4*.
• *Runx2* suppressed Wnt inhibitor expression (*Axin2*, *Drapc1*) in the dental mesenchyme.

Conclusions:

• Increased mesenchymal Wnt signaling inhibits sequential tooth formation.
• Antagonistic interactions between *Axin2* and *Runx2* modulate mesenchymal Wnt/β-catenin signaling levels.
• These interactions explain the divergent dental phenotypes observed in human *AXIN2* and *RUNX2* mutations.