<i>Kdf1</i> Regulates Molar Cusp Morphogenesis via the <scp>PI3K</scp> / <scp>AKT</scp> / <scp>mTOR</scp> Signalling Axis

Keratinocyte differentiation factor 1 (Kdf1) reportedly plays a significant role in enamel formation. In terms of tooth morphogenesis, human KDF1 variants are associated with crown morphological abnormalities, suggesting that Kdf1 may also be essential for tooth morphogenesis. However, the involvement of Kdf1 in tooth morphogenesis and its underlying mechanisms remains unclear. In this study, we observed that mice lacking epithelial Kdf1 (K14-Cre;Kdf1 ^fl/fl ) displayed rounded and blunt molar cusps, resembling the morphological anomalies observed in patients with Kdf1 variants. 5-Ethynyl-2'-deoxyuridine assays revealed increased proliferative activity of the inner enamel epithelial (IEE) cells in the cusp region of K14-Cre;Kdf1 ^fl/fl mice during the bell stage. RNA sequencing and western blot analysis confirmed the overactivation of PI3K/AKT/mTOR signalling in the molar IEE cells of K14-Cre;Kdf1 ^fl/fl mice. Furthermore, in utero microcapillary injection of the PI3K/AKT/mTOR pathway inhibitor LY294002 partially rescued the molar cusp defects in K14-Cre;Kdf1 ^fl/fl mice. Collectively, our findings provide in vivo evidence supporting the regulatory role of Kdf1 in molar cusp morphogenesis, highlighting its function in modulating dental epithelial cell proliferation via the PI3K/AKT/mTOR signalling pathway.