Tooth enamel is the hardest substance in the human body, protecting teeth from wear, temperature changes, and cavities. However, once enamel is damaged, it cannot be regenerated. Genetic disorders such as enamel hypoplasia interfere with the formation of enamel during development, leaving affected people’s teeth brittle, discolored, and susceptible to cavities. Several genes are thought to be associated with this condition, but the mechanisms by which specific mutations impair enamel-forming cells remain unclear.
The research team tackling this challenge was led by Professor Wei Zhao and Professor Dongsheng Yu from the Department of Oral Emergency Medicine, Guanghua School of Stomatology, Guangdong Key Research Institute of Stomatology, Sun Yat-Sen University, Guangzhou, China. Researchers found that patient-derived keratinocyte differentiation factor 1 (KDF1) mutation, p.R303P, previously associated with inherited enamel defects.
They used genetically engineered mice, molecular analysis, imaging techniques, and experiments on dental epithelial cells to investigate how the mutations disrupt tooth development. Their findings were published in Volume 18 of the journal. International Journal of Oral Sciences May 21, 2026.
The team first investigated KDF1 Activities during tooth development. they discovered it KDF1 is highly expressed in dental epithelial cells and is closely associated with cell-cell contact areas, suggesting a role in the maintenance of epithelial tissue. Variations did not decrease KDF1 This suggests disruption of cellular interactions essential for enamel formation.
To assess the impact of the mutations, the researchers KDF1. Both groups developed enamel abnormalities, with the most severe defects observed in homozygous animals. Analysis revealed enamel thinning, decreased mineral density, abnormal enamel prismatic structure, and delayed tooth eruption. The mutant mice also had reduced levels of key enamel proteins and enzymes, including amelogenin, ameloblastin, and matrix metalloproteinase 20, which are required for enamel secretion and maturation.
Further experiments showed that this mutation disrupted the adhesive structures that connect ameloblasts, the cells responsible for producing enamel. Levels of important adhesion molecules such as E-cadherin and integrin β4 were significantly reduced. Weakened adhesion disrupted the regulation of the Hippo pathway, leading to excessive accumulation of YAP in the nucleus. This activated genes that promote cell proliferation. Rather than maturing into amelogenic cells, the mutant ameloblasts remained in a proliferative state and failed to differentiate properly.
Our findings revealed that KDF1 is much more than a structural protein. It acts as a key coordinator linking cell adhesion to signaling pathways that control whether ameloblasts continue to divide or mature to form enamel. When this balance is disrupted, enamel development is severely impaired. ”
Mr. Wei Zhao, Professor, Oral Emergency Department, Guanghua Stomatology University, Stomatology Hospital
The researchers then tested whether correcting this signaling imbalance could improve enamel development. By using verteporfin, a drug that inhibits the YAP-TEAD1 interaction, they partially reversed the abnormal cell behavior. Treated cells showed reduced proliferation and improved differentiation, whereas mutant mice showed increased enamel volume. Although enamel mineralization was not completely reversed, this finding showed that the disease process could be therapeutically modified.
“This study provides a strong foundation for developing targeted treatments for inherited enamel diseases.” said Professor You.By identifying drug-responsive pathways, we have opened new opportunities to apply basic developmental biology to future clinical interventions. ”
Its influence extends beyond dentistry. Because cell adhesion and Hippo-YAP signaling control tissue growth in many organs, this discovery has the potential to stimulate collaborative research in regenerative medicine, stem cell biology, tissue engineering, craniofacial research, and precision medicine. In the short term, this study may improve our understanding of the genetic basis of enamel diseases and support earlier diagnosis. In the long term, these insights may contribute to treatments that preserve, repair, or regenerate tooth tissue, improving oral health outcomes for future generations.
Overall, this study revealed a previously unknown mechanism responsible for the disease. KDF1 Mutations leading to enamel defects due to disruption of cell adhesion and Hippo-YAP signaling. By showing that these abnormalities can be partially rescued by pharmacological intervention, researchers provide new insights into tooth development and a promising path toward future treatments for inherited enamel diseases.
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Reference magazines:
Lee, P. others. (2026) Kdf1 missense mutations caused enamel defects by disrupting cell adhesion and Hippo-YAP signaling in the dental epithelium. International Journal of Oral Sciences. DOI: 10.1038/s41368-026-00445-4.
