Kdf1 Regulates Molar Cusp Morphogenesis via the PI3K/AKT/mTOR Signalling Axis

Area of Science:

• Developmental biology
• Oral biology
• Molecular genetics

Background:

• Keratinocyte differentiation factor 1 (Kdf1) is implicated in enamel formation.
• Human KDF1 variants are linked to dental crown abnormalities, suggesting a role in tooth morphogenesis.
• The precise function and mechanisms of Kdf1 in tooth morphogenesis are not fully understood.

Purpose of the Study:

• To investigate the role of Kdf1 in tooth morphogenesis, specifically molar cusp development.
• To elucidate the molecular mechanisms underlying Kdf1's function in dental epithelial cells.

Main Methods:

• Generation of mice lacking epithelial Kdf1 (K14-Cre;Kdf1^fl/fl).
• Analysis of molar cusp morphology and cell proliferation using EdU assays.
• RNA sequencing and Western blot to assess signaling pathway activation.
• Pharmacological inhibition of the PI3K/AKT/mTOR pathway in vivo.

Main Results:

• Mice lacking Kdf1 exhibited rounded, blunt molar cusps, mirroring human KDF1 variant phenotypes.
• Increased proliferation of inner enamel epithelial (IEE) cells was observed in Kdf1-deficient mice.
• Overactivation of the PI3K/AKT/mTOR signaling pathway was confirmed in IEE cells of Kdf1-deficient mice.
• Inhibition of the PI3K/AKT/mTOR pathway partially rescued molar cusp defects.

Conclusions:

• Kdf1 plays a vital regulatory role in molar cusp morphogenesis.
• Kdf1 modulates dental epithelial cell proliferation through the PI3K/AKT/mTOR signaling pathway.
• This study provides in vivo evidence for Kdf1's essential function in tooth development.