牙颌发育模式及分子机制

牙颌发育模式及分子机制是理解牙颌结构功能的前提，也是再生牙颌组织器官的基础。牙发育分为牙胚发育期、牙冠形成期和牙根形成期。在这一过程中，关键基因具有时间空间的序列性表达。牙源性上皮和间充质相互作用以及釉结等特殊细胞群对牙冠形态精细化、个性化调控，发育成牙。在生物应力、信号调控机制下，牙顺利萌出并发挥功能。牙和颌骨同处发育之中，相互独立又相互依存，相互调控共同发育成为一个有机的整体。牙和颌骨均起源于第一鳃弓，牙或颌骨的发育异常通常会导致彼此的发育缺陷。本文评述牙和颌骨发育的过程，首次阐述稳态微环境在牙发育中的作用以及重点关注颌骨发育中以梅克尔软骨为代表的典型结构和特殊的信号调控机制，提出牙颌一体化发育模式，动态解析牙和颌骨一体化发育过程，并期待未来将这些新模式和机制运用于组织再生。     

初级纤毛在牙发育中的分布及相关信号通路的研究进展

初级纤毛是位于大多数哺乳动物细胞表面,感受外环境刺激并传导信息的一种细胞器,在组织发育过程中参与调控各种信号通路。本文就初级纤毛在牙发育中的分布及相关信号通路的研究进展作一综述。文献复习结果表明,在牙发育过程中,初级纤毛在上皮与间充质的相互诱导中发挥重要作用,且随细胞不断增殖分化,初级纤毛的分布呈现出时间和空间依赖性。尽管此分布特征的原因尚不明确,但部分实验证据表明其与初级纤毛所分布的细胞与组织的功能相适应。初级纤毛在牙发育过程中主要参与调控Hedgehog和Wnt两种重要的信号通路,编码纤毛蛋白的基因(如Kif3a、Evc/Evc2和Ift等)可通过对这两种信号通路的调控来影响牙齿的发育,并且两种信号通路之间存在交互作用。相关基因(如Ofd1,Bbs等)的缺失也可通过损害纤毛的结构或功能破坏上下游信号的传导,引起多种类型的牙齿发育不良,包括小牙、釉质发育不全、牙齿缺失或颅面部畸形。     

孕期健康和环境暴露对牙发育的影响

牙发育是复杂信号网络调控的牙源性上皮和神经嵴来源牙源性间充质之间交互作用的结果,遗传因素及环境因素在此过程中均发挥重要作用。母体是胎儿生长发育的主要载体,孕期母体健康和环境暴露对胎儿和儿童牙发育具有较大影响。本文根据不同类型的孕期母体环境因素,重点从环境内分泌干扰物、多种化学物质的联合作用及母体健康等三个方面对胎儿和儿童牙发育的关键问题进行综述,探讨了孕期环境因素在釉质发育缺陷、磨牙切牙矿化不全、氟牙症、多生牙及先天性缺牙等牙发育异常中的作用,为从生命早期预防牙发育异常、评估牙发育异常风险、进行牙发育相关咨询、促进儿童口腔健康管理提供理论依据。     

Wnt信号通路相关基因在颌骨牙源性角化囊性瘤中的表达及意义

目的研究Wnt信号通路相关基因在颌骨牙源性角化囊性瘤中的表达,探讨其发挥的调控作用。方法收集颌骨牙源性角化囊性瘤新鲜标本及同一患者的正常口腔黏膜,提取RNA,基因芯片检测Wnt信号通路的相关基因,进行生物信息学分析。结果颌骨牙源性角化囊性瘤与正常口腔黏膜相比,在Wnt信号通路相关基因中发现5个共同差异表达基因,其中CAMK2A下调, FZD3、MAPK10、PRKX、WNT5a上调。结论牙源性角化囊性瘤中存在Wnt信号通路基因的异常表达,Wnt信号通路相关基因在颌骨牙源性角化囊性瘤中发挥一定的调控作用。     

Wnt信号通路与牙胚发育

牙齿的发生、分化是牙源性上皮与外胚间充质相互诱导、相互作用的结果。牙胚发育过程中复杂的信号调控体系是近年来口腔科学研究领域的难点和热点。现已初步证实Wnt信号通路是参与牙胚发育过程重要的分子信号调控因子。在牙胚发育过程中,随着Wnt信号通路调控机制的阐明,必将为牙再生的研究提供理论基础。该文就近几年对Wnt信号通路与牙胚发育关系的研究作一综述。     

axin-2与牙发育的关系

axin是1997年发现的编码Axin蛋白的基因,该家族成员包括axin-1和axin-2。axin-2作为Wnt信号通路中的负调节因子,参与胚胎发育、细胞分化和器官形成等生理进程。牙发育过程同样受到严格的基因调控,基因的异常表达可能导致牙发育异常。有研究报道,axin-2可能与先天性缺牙有关,此外还与各类肿瘤发生密切相关,被认为是肿瘤抑制基因。下面就axin-2的结构、生物学特性、与牙发育关系等内容作一综述。     

Notch信号在牙胚发育中的调控机制

Notch信号通路是一种高度保守的细胞间信号传导机制,该信号激活后,可通过＂旁诱导效应＂调控自身和周围干（祖）细胞的分化、增殖。Notch信号的正常表达和激活对于牙胚发育、牙齿的形成和萌出十分重要。在牙胚发育的不同时期,牙源性上皮和间充质中的Notch信号因子受到生长因子（FGFs、BMPs等）的调控,会得到不同程度的表达和维持,从而在成牙本质细胞及成釉细胞的分化、牙体硬组织的矿化、牙尖发育模式的形成和牙根的形成等一系列发育过程中发挥重要作用。     

骨形态发生蛋白信号通路在牙根发育中的作用

骨形态发生蛋白（BMP）家族是调节细胞生命活动的重要因子,几乎参与了所有组织的发育。BMP介导的信号通路在牙发育过程中发挥十分重要的作用,而牙根发育是牙发育的一部分,是上皮和间充质相互作用的复杂过程。上皮和牙胚间充质中的BMP信号通路在牙根发育中的作用也有所不同,本文综述了BMP信号通路在牙根发育中作用的研究进展。     

表观遗传在牙发育中的作用

表观遗传是指DNA序列不发生变化,基因的表达方式发生了可遗传改变的一种遗传方式,主要包括DNA甲基化、组蛋白修饰和非编码RNA调控等。在牙发育过程中,传统基因调控与表观遗传学调控共同参与协同,调节细胞增殖分化相关基因的时空表达。探索牙发育过程中的表观遗传调控机制,可为牙再生提供线索和思路,本文主要对表观遗传调控在牙发育...     

初级纤毛对牙发育的作用及相关机制的研究进展

初级纤毛是哺乳动物细胞表面特化的细胞突起,其内部存在大量调控细胞生命活动的信号分子,参与构成细胞内的信息传递系统。近年来研究发现,牙组织细胞有纤毛存在,并且纤毛病患者可同时伴有牙齿发育异常表现。说明细胞纤毛可能参与牙发育过程。本文旨在将近年来国内外有关初级纤毛在牙齿发育中的功能及作用机制研究进展作一综述,阐示细胞纤毛中信号分子的功能及作用通路,拓展对牙发育机制的了解。     

Immunohistochemical detection of β-catenin and adenomatous polyposis coli in ameloblastomas

BACKGROUND: To clarify the roles of the Wnt signaling pathway in oncogenesis and cytodifferentiation of odontogenic tumors, expression of beta-catenin and adenomatous polyposis coli (APC) was analyzed in ameloblastomas as well as in tooth germs. METHODS: Tissue specimens of 10 tooth germs, 40 benign ameloblastomas, and five malignant ameloblastomas were examined immunohistochemically with the use of antibodies against beta-catenin and APC. RESULTS: Immunohistochemical reactivity for beta-catenin was detected in the cell membrane and cytoplasm of most odontogenic epithelial cells in tooth germs and ameloblastomas. Nuclear beta-catenin expression was recognized in nine of 40 ameloblastomas and two of five malignant ameloblastomas, but not in tooth germs. APC was evidently expressed in odontogenic epithelial cells neighboring the basement membrane in tooth germs and ameloblastomas, and the reactivity was significantly lower in benign and malignant ameloblastomas than in tooth germs. Follicular ameloblastomas and acanthomatous ameloblastomas tended to show high nuclear beta-catenin expression and low APC reactivity, as compared with other ameloblastoma variants. CONCLUSION: Expression of beta-catenin and APC in tooth germs and ameloblastomas suggests that aberration of the Wnt signaling pathway might play a role in oncogenesis and cytodifferentiation of odontogenic epithelium via deregulation of cell proliferation.     

Immunohistochemical detection of phosphorylated Akt, PI3K, and PTEN in ameloblastic tumors

OBJECTIVE: To evaluate roles of the Akt signaling pathway in oncogenesis and cytodifferentiation of odontogenic tumors, expression of phosphorylated Akt (pAkt), PI3K, and PTEN was analyzed in ameloblastic tumors as well as in tooth germs. METHODS: 11 tooth germs, 40 ameloblastomas, and 5 malignant ameloblastic tumors were examined immunohistochemically with antibodies against pAkt, PI3K, and PTEN. RESULTS: Immunoreactivity for pAkt, PI3K, and PTEN was detected predominantly in odontogenic epithelial cells near the basement membrane in tooth germs and ameloblastic tumors. The levels of immunoreactivity for pAkt and PI3K were slightly higher in ameloblastic tumors than in tooth germs. Plexiform ameloblastomas showed significantly higher expression of PI3K than follicular ameloblastomas, and PI3K immunoreactivity in ameloblastomas without cellular variation was significantly higher than that in acanthomatous ameloblastomas. The level of PTEN immunoreactivity was significantly lower in ameloblastomas than in tooth germs. CONCLUSION: Expression of pAkt, PI3K, and PTEN in tooth germs and ameloblastic tumors suggests that these signaling molecules regulate cell survival and growth in normal and neoplastic odontogenic tissues by mediating growth factor signals. Increased expression of pAkt and PI3K and decreased expression of PTEN in ameloblastic tumors may participate in oncogenesis of odontogenic epithelium by activating the Akt signaling pathway.     

Hippo-TAZ/YAP信号通路在头颈部鳞状细胞癌中的研究进展

Hippo信号通路是近年来新发现的一个高度保守的蛋白激酶级联通路。其中,TAZ/YAP是该信号通路中核心的效应分子。大量研究证实,TAZ/YAP与人类大多数恶性肿瘤的发生或生长密切相关,其异常活化可促进肿瘤细胞增殖、侵袭转移、增强化疗耐药及获得干细胞样特性。近年来研究表明,TAZ/YAP异常活化与头颈部肿瘤的发生发展密切相关,其有可能作为头颈部肿瘤治疗的潜在靶点。本文综述Hippo通路的最新研究进展,重点关注的是该通路中的TAZ/YAP在头颈部鳞状细胞癌中的调控作用,为头颈部鳞状细胞癌的研究和治疗提供新的思路和策略。     

K-Ras gene status and expression of Ras/mitogen-activated protein kinase (MAPK) signaling molecules in ameloblastomas

BACKGROUND: To clarify the roles of rat sarcoma (Ras)/mitogen-activated protein kinase (MAPK) signaling pathway in oncogenesis and cytodifferentiation of odontogenic tumors, K-Ras gene status and expression of Ras, Raf1, MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)1, and ERK1/2 proteins were analyzed in ameloblastomas as well as in tooth germs. METHODS: Paraffin sections of 10 tooth germs and 46 benign and 6 malignant ameloblastomas were examined immunohistochemically for the expression of K-Ras, Raf1, MEK1, and ERK1/2. Frozen tissue samples of 22 benign ameloblastomas and 1 malignant (metastasizing) ameloblastoma were analyzed by direct DNA sequencing to detect K-Ras gene alteration. RESULTS: Immunohistochemical reactivity for K-Ras, Raf1, MEK1, and ERK1/2 was detected in both normal and neoplastic odontogenic epithelium, and these molecules were reactive chiefly with odontogenic epithelial cells neighboring the basement membrane. Plexiform ameloblastomas showed slightly stronger expression of these Ras/MAPK signaling molecules than follicular ameloblastomas. Keratinizing cells and granular cells showed decreased reactivity for the signaling molecules. Basal cell ameloblastomas showed slightly stronger reactivity for the signaling molecules than did the other subtypes. K-Ras immunoreactivity in malignant ameloblastomas was lower than that in dental lamina of tooth germs. Direct DNA sequencing showed a GGT to GCT point mutation at codon 12 of K-Ras gene in one ameloblastoma. Conclusion: Expression of K-Ras, Raf1, MEK1, and ERK1/2 in tooth germs and ameloblastomas suggests that Ras/MAPK signaling pathway functions to regulate cell proliferation and differentiation in both normal and neoplastic odontogenic epithelium. K-Ras gene status implied that K-Ras mutations might play a minor role in oncogenesis of odontogenic epithelium.     

BMP activity is required for tooth development from the lamina to bud stage

Several Bmp genes are expressed in the developing mouse tooth germ from the initiation to the late-differentiation stages, and play pivotal roles in multiple steps of tooth development. In this study, we investigated the requirement of BMP activity in early tooth development by transgenic overexpression of the extracellular BMP antagonist Noggin. We show that overexpression of Noggin in the dental epithelium at the tooth initiation stage arrests tooth development at the lamina/early-bud stage. This phenotype is coupled with a significantly reduced level of cell proliferation rate and a down-regulation of Cyclin-D1 expression, specifically in the dental epithelium. Despite unaltered expression of genes known to be implicated in early tooth development in the dental mesenchyme and dental epithelium of transgenic embryos, the expression of Pitx2, a molecular marker for the dental epithelium, became down-regulated, suggesting the loss of odontogenic fate in the transgenic dental epithelium. Our results reveal a novel role for BMP signaling in the progression of tooth development from the lamina stage to the bud stage by regulating cell proliferation and by maintaining odontogenic fate of the dental epithelium.     

Expression and roles of CCN2 in dental mesenchymal cells in primary culture—With findings in a case of odontogenic myxofibroma

Purpose of the researchTooth germ development involves multiple events, including cell proliferation and cell differentiation. Connective tissue growth factor (CTGF/CCN2) is a signaling protein involved in tooth germ development, and we investigated how it is expressed and what roles it may have in primary cultures of mesenchymal cells derived from the developing tooth germ. We also examined the expression of CCN2 in a human odontogenic myxofibroma, a benign tumor of odontogenic mesenchymal origin, and considered the possible roles of CCN2 in the development of myxofibromas.Materials and methodsMesenchymal cells of early bell-stage tooth germs were isolated from Day-90 bovine embryos and placed in primary culture. A resected specimen from a patient with odontogenic myxofibroma was prepared for immunohistochemical studies.Principal resultsThe CCN2 expression level in proliferating odontogenic mesenchymal cells freshly isolated from the early bell stage of developing bovine tooth germs and placed in primary culture was 3 times higher than that in the confluent non-proliferating cells. Recombinant CCN2 significantly increased the proliferation and type I collagen expression in odontogenic mesenchymal cells in primary culture. Immunohistochemical analysis on myxofibroma case revealed that CCN2 was detectable in MIB-1, a cellular marker of proliferation-positive odontogenic mesenchymal cells adjacent to capillary blood vessels and in the endothelial cells of the vessels in the tumor.Major conclusionCCN2 signaling would influence the proliferation of and extracellular matrix production by dental mesenchymal cells. Our results suggest that the same mechanisms of CCN2 action toward dental mesenchymal cells would also be operative in the odontogenic myxofibroma microenvironment.     

Hippo/YAP信号通路与细胞增殖相关信号通路交叉作用的研究进展

Hippo/YAP信号通路首次被发现于果蝇中,在哺乳动物中具有高度保守的特性,可通过直接或间接地调节细胞增殖、程序性细胞死亡以起到平衡机体内环境稳态、维持器官大小的作用.YAP作为Hippo信号通路中的一个转录共激活因子,与磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(AKT)、Wnt/β-联蛋白、细胞外信号调节激酶(ERK) 1/2等通路中相关分子相互作用,使得Hippo通路与其他增殖调控相关信号通路形成“交通”,构成一个复杂的信号通路网,共同调控细胞的增殖.本文就目前对Hippo信号通路中共激活因子YAP与增殖调控信号通路间的交叉影响及其机制的研究进展作一综述.     

Immunohistochemical detection of hepatocyte growth factor, transforming growth factor-β and their receptors in epithelial odontogenic tumors

BACKGROUND: Tumors derived from odontogenic epithelium exhibit considerable variation and are classified into several benign and malignant entities. To clarify the role of growth factors in oncogenesis, cytodifferentiation and progression of epithelial odontogenic tumors, expression of hepatocyte growth factor (HGF), transforming growth factor-beta (TGF-beta) and their receptors were analyzed in these tumors as well as in tooth germs. METHODS: Specimens of five tooth germs, 34 ameloblastomas, three calcifying epithelial odontogenic tumors (CEOTs), two clear cell odontogenic tumors (CCOTs), five adenomatoid odontogenic tumors (AOTs), six calcifying odontogenic cysts (COCs) and six malignant ameloblastomas were examined immunohistochemically with the use of antibodies against HGF, TGF-beta and their receptors. RESULTS: In tooth germs and epithelial odontogenic tumors, immunoreactivity for HGF and TGF-beta was detected in both epithelial and mesenchymal cells, while expression of their receptors was found only in epithelial cells. In tooth germs and main types of ameloblastomas, HGF and TGF-beta reactivity was marked in epithelial cells near the basement membrane, and their receptors were diffusely positive in most epithelial cells. In subtypes of ameloblastomas, reduced expression of HGF, c-Met and TGF-beta and increased reactivity for TGF-beta receptors were detected in keratinizing cells in acanthomatous ameloblastomas, and granular cells in granular cell ameloblastomas demonstrated little or no expression of HGF, TGF-beta or their receptors. As compared with main types of ameloblastomas, basal cell ameloblastomas showed high HGF reactivity, and desmoplastic ameloblastomas exhibited elevated reactivity for TGF-beta and its receptors. Neoplastic cells in CEOTs, AOTs and COCs showed reactivity for HGF, TGF-beta and their receptors. Elevated HGF and TGF-beta reactivity was found in pseudoglandular cells in AOTs, and high expression of their receptors was noted in ghost cells in COCs. Metastasizing ameloblastomas showed similar expression patterns of HGF, TGF-beta and their receptors to those of benign ameloblastomas, while CCOTs and ameloblastic carcinomas had increased HGF expression and low reactivity for TGF-beta and its receptors as compared with benign ameloblastomas. CONCLUSIONS: Immunohistochemical localization of HGF, TGF-beta and their receptors in tooth germs and epithelial odontogenic tumors supports the hypothesis that HGF and TGF-beta act on epithelial cells via paracrine and autocrine mechanisms. Altered expression of the agents in these epithelial odontogenic tumors, especially subtypes of ameloblastomas, AOTs and COCs, suggests that HGF and TGF-beta signaling might affect differentiation of neoplastic odontogenic epithelial cells. Activated HGF/c-Met pathway and reduced TGF-beta signaling in CCOTs and ameloblastic carcinomas may be associated with the malignant potential of these epithelial odontogenic tumors.     

Dkk-Wnt信号通路在牙齿发育中作用的研究进展

哺乳动物的牙齿发育是外胚层上皮与间充质间相互调控和信号交流的结果,其中Dkk-Wnt信号通路是近年来牙胚发育研究领域的热点。Dkk-Wnt信号通路已被证实在牙体形成细胞功能的发挥、牙齿模式化、形态发生、牙冠钙化过程中扮演重要作用。牙齿发生发育分子机制的深入研究,将为牙再生组织工程技术以及相关技术的临床转化提供理论基础。本文就近十年对Wnt信号通路在牙齿发育中所起作用的研究作一综述。