Kdf1 missense mutation caused enamel defects by disrupting cell adhesion and Hippo-YAP signaling in dental epitheliumOA
Amelogenesis imperfecta is a hereditary enamel defect arising from dental epithelium dysfunction.Although keratinocyte differentiation factor 1(KDF1)acts as an intracellular regulator in epithelial cells,the underlying disease mechanism of the patient-derived KDF1 missense mutation in amelogenesis remains unclear.Here,we show that a patient-derived KDF1 mutation(c.908 G>C,p.R303P)causes enamel defects by disrupting cell adhesion and Hippo-YAP signaling.Immunohistochemistry revealed strong KDF1 expression throughout dental epithelium development,particularly at the cell membrane.Kdf1 mutation knock-in heterozygotes and homozygotes displayed graded defective enamel with reduced thickness,inadequate mineralization and disorganized microstructure.This phenotype correlated with a gradual reduction in enamel matrix proteins and proteases across genotypes.Bulk RNA sequencing of ameloblasts suggested marked changes in adhesion-related genes and the Hippo-YAP pathway.We characterized cellular consequences of this variant using both LS8 and ALC cell lines,which appeared abnormalities including accelerated proliferation,undermined differentiation,weakened adhesion,and enhanced migration.In vivo and in vitro findings supported a model wherein the KDF1 mutation impaired intercellular and cell-matrix adhesion in ameloblasts.As a result,ameloblast differentiation was hampered through excessive nuclear yes-associated protein(YAP)accumulation and overactivation of downstream proliferative genes.Pharmacological blockade of YAP and TEA domain family member 1(TEAD1)interaction rescued the mutant phenotypes.Taken together,Kdf1 mutation compromised murine amelogenesis through adhesion defects and subsequent Hippo-YAP dysregulation.
Pei Li;Runling Zeng;Jingyan Xue;Yaling Song;Jie Wu;Binghui Zeng;Ling Lin;Dongsheng Yu;Wei Zhao
Guanghua School of Stomatology,Hospital of Stomatology,Guangdong Provincial Key Laboratory of Stomatology,Sun Yat-Sen University,Guangzhou,ChinaGuanghua School of Stomatology,Hospital of Stomatology,Guangdong Provincial Key Laboratory of Stomatology,Sun Yat-Sen University,Guangzhou,ChinaGuanghua School of Stomatology,Hospital of Stomatology,Guangdong Provincial Key Laboratory of Stomatology,Sun Yat-Sen University,Guangzhou,ChinaState Key Laboratory of Oral&Maxillofacial Reconstruction and Regeneration,Key Laboratory of Oral Biomedicine Ministry of Education,Hubei Key Laboratory of Stomatology,School&Hospital of Stomatology,Wuhan University,Wu Han,ChinaGuanghua School of Stomatology,Hospital of Stomatology,Guangdong Provincial Key Laboratory of Stomatology,Sun Yat-Sen University,Guangzhou,ChinaGuanghua School of Stomatology,Hospital of Stomatology,Guangdong Provincial Key Laboratory of Stomatology,Sun Yat-Sen University,Guangzhou,ChinaGuanghua School of Stomatology,Hospital of Stomatology,Guangdong Provincial Key Laboratory of Stomatology,Sun Yat-Sen University,Guangzhou,ChinaGuanghua School of Stomatology,Hospital of Stomatology,Guangdong Provincial Key Laboratory of Stomatology,Sun Yat-Sen University,Guangzhou,ChinaGuanghua School of Stomatology,Hospital of Stomatology,Guangdong Provincial Key Laboratory of Stomatology,Sun Yat-Sen University,Guangzhou,China
医药卫生
epithelial cellstheintracellular regulatordental epithelium dysfunctionalthoughenamel defectkeratinocyte differentiation factoramelogenesis imperfectaKDF mutation
《International Journal of Oral Science》 2026 (3)
P.561-572,12
supported by the National Natural Science Foundation of China(Grant no.82571048)the Guangdong Basic and Applied Basic Research Foundation(Grant no.2026A1515010688)。
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