Xu Xun, Jeong Lesley, Han Jun, Ito Yoshihiro, Bringas Pablo, Chai Yang
Center for Craniofacial Molecular Biology School of Dentistry University of Southern California, Los Angeles, California 90033, USA.
Int J Dev Biol. 2003 Feb;47(1):31-9.
Members of the transforming growth factor-beta family (e.g. TGF-beta, BMP and activin) are critical regulators of tooth morphogenesis. The basic TGF-beta signaling engine consists of a receptor complex that activates Smads and a Smad-containing complex that controls transcription of the downstream target genes. Little is known about the expression of endogenous Smads during tooth morphogenesis. Using a cRNA probe or antibody which specifically recognizes the expression of each Smad molecule, we provide a comprehensive endogenous Smad expression analysis during tooth morphogenesis. BMP signaling is transmitted through Smad1 and 5 which are first expressed within the dental lamina and later expand into condensed dental mesenchyme at the bud stage. As tooth development advances into the cap and bell stage, BMP signaling Smads are strongly localized within the inner enamel epithelium (IEE) and cranial neural crest derived dental mesenchyme (DM), indicating their critical role in regulating epithelial-mesenchyme interaction during tooth morphogenesis. Smad2 and 3 are responsible for transmitting TGF-beta/activin signaling and show unique expression patterns during tooth morphogenesis. They are localized within the nuclei of both IEE and DM, suggesting that TGF-beta-activated Smads are critical for regulating tooth development. Smad4, the common Smad, is expressed in both dental epithelium and mesenchyme throughout all stages of tooth morphogenesis. The expression of inhibitory Smads (Smad6 and 7) largely overlaps with receptor regulated Smads, indicating that negative feedback on BMP/TGF-beta signaling is critical throughout all stages of tooth morphogenesis. Our results suggest that both receptor-regulated and inhibitory Smads are important regulators of tooth morphogenesis. The selective activation of Smad, as indicated by nucleartranslocation, may suggest selective activation of different members of the TGF-beta superfamily during tooth development.
转化生长因子-β家族成员（如TGF-β、骨形态发生蛋白（BMP）和激活素）是牙齿形态发生的关键调节因子。基本的TGF-β信号传导机制由激活Smad的受体复合物和控制下游靶基因转录的含Smad复合物组成。关于牙齿形态发生过程中内源性Smad的表达知之甚少。我们使用能特异性识别每个Smad分子表达的cRNA探针或抗体，对牙齿形态发生过程中的内源性Smad表达进行了全面分析。BMP信号通过Smad1和Smad5传导，它们首先在牙板中表达，随后在芽期扩展到凝聚的牙间充质中。随着牙齿发育进入帽状期和钟状期，BMP信号Smad强烈定位于内釉上皮（IEE）和颅神经嵴来源的牙间充质（DM）中，表明它们在牙齿形态发生过程中调节上皮-间充质相互作用方面起关键作用。Smad2和Smad3负责传导TGF-β/激活素信号，并在牙齿形态发生过程中表现出独特的表达模式。它们定位于IEE和DM的细胞核内，表明TGF-β激活的Smad对调节牙齿发育至关重要。共同的Smad Smad4在牙齿形态发生的所有阶段都在牙上皮和间充质中表达。抑制性Smad（Smad6和Smad7）的表达与受体调节的Smad在很大程度上重叠，表明对BMP/TGF-β信号的负反馈在牙齿形态发生的所有阶段都至关重要。我们的结果表明，受体调节的Smad和抑制性Smad都是牙齿形态发生的重要调节因子。如核转位所示的Smad的选择性激活，可能表明在牙齿发育过程中TGF-β超家族的不同成员被选择性激活。
