Mesenchymal Sufu Regulates Development of Mandibular Molar via Shh Signaling
Mesenchymal Sufu Regulates Development of Mandibular Molar via Shh Signaling
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间充质 Sufu 通过 Shh 信号调节下颌磨牙的发育
DOI：
10.1177/0022034519872679
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发表时间：
2019-09-09
影响因子：
7.6
通讯作者：
Zhang, Z.
中科院分区：
文献类型：
--
作者：
Li, J.;Xu, J.;Zhang, Z.
牙齿上皮中的Sonic刺猬（SHH）通过上皮 - 间质信号传导调节牙齿形态发生。但是，在此过程中，SHH信号调节的作用尚不清楚。在这里，我们发现SHH信号的主要负调节器的融合（Sufu）的间充质抑制剂在调节芽型胶流阶段过渡期间调节牙齿胚芽形态发生方面起着重要作用。 Dermo1-Cre小鼠在牙科间充质中的SUFU删除导致下颌磨牙延迟发展为盖阶段，而原始搪瓷结（EK）形成缺陷。我们显示了Sufu突变体牙齿上皮和间质的细胞增殖和程序性细胞死亡的破坏。 E14.5的牙齿胚芽的双侧基底细胞中，上皮特异性粘附分子E-钙粘着蛋白显然会降低。假定EK中的细胞（主要表达p-钙粘蛋白）似乎分层但无法凝结。此外，与对照组相比，主要EK标记基因（包括SHH，FGF4和P21）的转录本显着降低。相反，我们发现SUFU的缺乏会导致间充质中SHH信号的升高，这是由GLI1和PTCH1的显着上调所表明的。同时，在牙科间质中，BMP4和FGF3的表达是间质上皮诱导的关键因素。此外，runx2的表达在芽阶段经历了短暂的降低。综上所述，这些数据表明，间充质SUFU对于调整SHH信号是必要的，SHH信号传导可能充当BMP4和FGF3的上游调节剂，以协调牙齿间充质和牙齿胚芽上皮之间的相互作用。
Sonic hedgehog (Shh) in dental epithelium regulates tooth morphogenesis by epithelial-mesenchymal signaling transduction. However, the action of Shh signaling regulation in this process is not well understood. Here we find that mesenchymal Suppressor of Fused (Sufu), a major negative regulator of Shh signaling, plays an important role in modulating the tooth germ morphogenesis during the bud-to-cap stage transition. Deletion of Sufu in dental mesenchyme by Dermo1-Cre mice leads to delayed development of mandibular molar into cap stage with defect of primary enamel knot (EK) formation. We show the disruption of cell proliferation and programmed cell death in dental epithelium and mesenchyme in Sufu mutants. Epithelial-specific adhesion molecule E-cadherin is evidently reduced in the bilateral basal cells of tooth germ at E14.5. The cells in the presumptive EK, predominantly expressing P-cadherin, appear stratified but fail to condense. Moreover, the transcripts of primary EK marker genes, including Shh, Fgf4, and p21, are significantly decreased compared to controls. In contrast, we find that deficiency of Sufu results in elevation of Shh signaling in mesenchyme, indicated by the significant upregulation of Gli1 and Ptch1. Meanwhile, the expression of Bmp4 and Fgf3, the critical factors of mesenchymal-epithelial induction, is significantly inhibited in dental mesenchyme. Furthermore, the expression of Runx2 experiences a transient decrease at the bud stage. Taken together, these data suggest that mesenchymal Sufu is necessary for tuning the Shh signaling, which may act as an upstream modulator of Bmp4 and Fgf3 to coordinate the interplay between the dental mesenchyme and epithelium of tooth germ.