Cdc42 deletion yielded enamel defects by disrupting mitochondria and producing reactive oxygen species in dental epithelium

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外文摘要：Developmental defects of enamel are common due to genetic and environmental factors before and after birth.Cdc42,a Rho family small GTPase,regulates prenatal tooth development in mice.However,its role in postnatal tooth development,especially enamel for-mation,remains elusive.Here,we investigated Cdc42 functions in mouse enamel development and tooth repair after birth.Cdc42 showed highly dynamic temporospatial patterns in the developing incisors,with robust expression in ameloblast and odontoblast layers.Strikingly,epithelium-specific Cdc42 deletion resulted in enamel defects in incisors.Ameloblast differen-tiation was inhibited,and hypomineralization of enamel was observed upon epithelial Cdc42 deletion.Proteomic analysis showed that abnormal mitochondrial components,phosphotrans-ferase activity,and ion channel regulator activity occurred in the Cdc42 mutant dental epithe-lium.Reactive oxygen species accumulation was detected in the mutant mice,suggesting that abnormal oxidative stress occurred after Cdc42 depletion.Moreover,Cdc42 mutant mice showed delayed tooth repair and generated less calcified enamel.Mitochondrial dysfunction and abnormal oxygen consumption were evidenced by reduced Apool and Timm8a1 expression,increased Atp5j2 levels,and reactive oxygen species overproduction in the mutant repair epithelium.Epithelium-specific Cdc42 deletion attenuated ERK1/2 signaling in the labial cer-vical loop.Aberrant Sox2 expression in the mutant labial cervical loop after clipping might lead to delayed tooth repair.These findings suggested that mitochondrial dysfunction,up-regulated oxidative stress,and abnormal ion channel activity may be among multiple factors responsible for the observed enamel defects in Cdc42 mutant incisors.Overall,Cdc42 exerts multidimen-sional and pivotal roles in enamel development and is particularly required for ameloblast dif-ferentiation and enamel matrix formation.

外文关键词：

Cdc42Enamel defectsMitochondrial dysfunctionRho GTPaseTooth repair

作者：

Jinxuan Zheng、Rongcheng Yu、Yiqi Tang、Sihui Su、Sainan Wang、Chenxi Liao、Xuecong Li、Jiabin Liao、Dongsheng Yu、Tingting Ai、Wei Zhao、Vicky Yau、Chufeng Liu、Liping Wu、Yang Cao

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作者单位：

Hospital of Stomatology,Guanghua School of Stomatology,Guangdong Provincial Key Laboratory of Stomatology,Sun Yat-sen University,Guangzhou,Guangdong 510055,China

Guangdong Provincial Key Laboratory of Oral Diseases,Guangzhou,Guangdong 510055,China

Department of Cariology and Endodontology,Peking University School and Hospital of Stomatology &National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices,Beijing 100081,China

Department of Oral and Maxillofacial Surgery,University at Buffalo,Buffalo,NY 14214,USA

Department of Orthodontics,Stomatological Hospital,Southern Medical University,Guangzhou,Guangdong 510280,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNatural Science Foundation of Guangdong Province,ChinaNatural Science Foundation of Guangdong Province,ChinaSun Yat-Sen University Clinical Research 5010 ProgramScience and Technology Planning Project of Guangzhou,ChinaOpen Funding of Guangdong Provincial Key Laboratory of Stomatology(China)

项目编号：

81900958821709878207337881974146821010532020A1515-0100592021A151501253520230092023-A04J2148KF2021120104

出版年：

2024

DOI：

10.1016/j.gendis.2023.101194

基因与疾病(英文)

ISSN：

年,卷(期)：2024.11(5)

参考文献量1