Zhang Jiayi, Gao Jingyi, Zeng Xiangliang, Wang Zijie, Chen Chuying, Rong Chao, Li Shaowei, Cai Lingxuan, Wang Luchen, Zhang Lin, Tian Zhihui
Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China; School of Stomatology, Southern Medical University, Guangzhou, Guangdong Province, China.
Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Tissue Construction and Detection, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Feb;1871(2):167570. doi: 10.1016/j.bbadis.2024.167570. Epub 2024 Nov 14.
Enamel formation is a developmental event governed by intricate molecular signal pathways. Cdc42 is proven to regulate enamel development yet its underlying role and molecular mechanism in early amelogenesis remain elusive. The extracellular matrix of tooth germ basement membrane is critical for the regulation of ameloblast differentiation. Present study investigated whether Cdc42 influences amelogenesis by affecting ECM synthesis and how Cdc42 regulates ameloblasts differentiation. Epithelial-specific knockout of Cdc42 (Cdc42-cKO) mice model was employed to study the ECM expression including Fibronectin (Fn) and amelogenesis markers. Cdc42-cKO mice results in retarded ameloblast differentiation and enamel matrix decrease. Fn synthesis in the enamel organ and basal membrane was totally diminished along with Cdc42 knockdown. YAP acting as the Cdc42 downstream transcription factor, its distribution in ameloblasts was synchronously attenuated by Cdc42 knockdown and nuclear localization progressively decreased with tooth germ development. Cdc42 unidirectionally controls the Fn synthesis via YAP regulation. Overall, ameloblast differentiation inhibition by silencing of Cdc42 was successfully rescued by YAP activation. We demonstrated that Cdc42 as an initiator, mediated downstream pathway through transcriptional activator YAP, thereby affecting ameloblast differentiation by controlling Fn synthesis. The Cdc42-YAP-Fn signaling axis are elucidated to act critical role during the early amelogenesis.
釉质形成是一个由复杂分子信号通路控制的发育过程。已证实Cdc42可调节釉质发育，但其在早期釉质发生中的潜在作用和分子机制仍不清楚。牙胚基底膜的细胞外基质对成釉细胞分化的调节至关重要。本研究调查了Cdc42是否通过影响细胞外基质合成来影响釉质发生，以及Cdc42如何调节成釉细胞分化。采用上皮特异性敲除Cdc42（Cdc42-cKO）小鼠模型来研究包括纤连蛋白（Fn）在内的细胞外基质表达和成釉发生标志物。Cdc42-cKO小鼠导致成釉细胞分化延迟和釉质基质减少。随着Cdc42敲低，釉器和基底膜中的Fn合成完全减少。YAP作为Cdc42的下游转录因子，其在成釉细胞中的分布随着Cdc42敲低而同步减弱，并且随着牙胚发育核定位逐渐减少。Cdc42通过YAP调节单向控制Fn合成。总体而言，通过激活YAP成功挽救了因沉默Cdc42而导致的成釉细胞分化抑制。我们证明，Cdc42作为启动子，通过转录激活因子YAP介导下游通路，从而通过控制Fn合成影响成釉细胞分化。阐明了Cdc42-YAP-Fn信号轴在早期釉质发生过程中起关键作用。
