Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
J Dent Res. 2013 Mar;92(3):222-8. doi: 10.1177/0022034512471826. Epub 2013 Jan 11.
Tooth morphogenesis involves patterning through the activity of epithelial signaling centers that, among other molecules, secrete Sonic hedgehog (Shh). While it is known that Shh responding cells need intact primary cilia for signal transduction, the roles of individual cilia components for tooth morphogenesis are poorly understood. The clinical features of individuals with Ellis-van Creveld syndrome include various dental anomalies, and we show here that absence of the cilial protein Evc in mice causes various hypo- and hyperplasia defects during molar development. During first molar development, the response to Shh signaling is progressively lost in Evc-deficient embryos and, unexpectedly, the response consistently disappears in a buccal to lingual direction. The important role of Evc for establishing the buccal-lingual axis of the developing first molar is also supported by a displaced activity of the Wnt pathway in Evc mutants. The observed growth abnormalities eventually manifest in first molar microdontia, disruption of molar segmentation and symmetry, root fusions, and delayed differentiation. Analysis of our data indicates that both spatially and temporally disrupted activities of the Shh pathway are the primary cause for the variable dental anomalies seen in patients with Ellis-van Creveld syndrome or Weyers acrodental dysostosis.
牙齿形态发生涉及上皮信号中心的模式形成，这些信号中心除其他分子外，还分泌 Sonic hedgehog（Shh）。虽然已知 Shh 反应细胞需要完整的初级纤毛进行信号转导，但个别纤毛成分在牙齿形态发生中的作用知之甚少。Ellis-van Creveld 综合征患者的临床特征包括各种牙齿异常，我们在这里表明，小鼠中纤毛蛋白 Evc 的缺失会导致磨牙发育过程中的各种增生和增生缺陷。在第一磨牙发育过程中，Evc 缺陷胚胎中 Shh 信号的反应逐渐丧失，出乎意料的是，反应一致地从颊侧向舌侧消失。Wnt 通路在 Evc 突变体中的活性移位也支持 Evc 对建立发育中第一磨牙颊舌轴的重要作用。观察到的生长异常最终表现为第一磨牙小牙症、磨牙分段和对称性破坏、根融合和分化延迟。我们数据分析表明，Shh 通路的空间和时间活动的破坏是 Ellis-van Creveld 综合征或 Weyers 肢端牙发育不良患者所见各种牙齿异常的主要原因。
