Restriction of sonic hedgehog signalling during early tooth development
Restriction of sonic hedgehog signalling during early tooth development
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DOI：
10.1242/dev.01163
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发表时间：
2004-06-01
期刊：
影响因子：
4.6
通讯作者：
Sharpe, PT
中科院分区：
文献类型：
--
作者：
Cobourne, MT;Miletich, I;Sharpe, PT
由超音刺猬基因编码的信号肽仅限于口腔上皮的局部增厚，这标志着牙齿发育的第一个形态学证据，并且在牙形成的开始过程中起着至关重要的作用。我们发现，在没有上皮的小鼠下颌弓的这些阶段，Shh靶点Ptc1和Gli1在间隙间质中上调，间隙间质是磨牙和门牙形成部位之间的无牙区域。这种异位表达与Shh转录无关，但与Shh蛋白有关，在上皮细胞中检测不到。这些发现表明，在纵膈间质中，Shh活性的限制依赖于上覆上皮。这种抑制活性通过移植牙膈上皮下调牙外植体Ptc1和离体牙膈间质表达Ptc1的能力得到证实。空胚间质的一个候选抑制剂是糖基磷脂酰肌醇连接的膜糖蛋白Gas1。Gas1通常在下颌弓间质中表达；然而，在没有上皮的情况下，这种表达在膈膜中特异性下调，在膈膜中发现异位Shh蛋白。虽然Shh信号对下颌弓间质中Gas1的表达没有影响，但Gas1的过表达会导致异位Ptc1的下调。因此，下颌弓中牙齿起始位置的控制涉及到Shh信号在需要牙齿的部位和在注定要保持无牙的区域的拮抗的组合。
The signalling peptide encoded by the sonic hedgehog gene is restricted to localised thickenings of oral epithelium, which mark the first morphological evidence of tooth development, and is known to play a crucial role during the initiation of odontogenesis. We show that at these stages in the murine mandibular arch in the absence of epithelium, the Shh targets Ptc1 and Gli1 are upregulated in diastema mesenchyme, an edentulous region between the sites of molar and incisor tooth formation. This ectopic expression is not associated with Shh transcription but with Shh protein, undetectable in the presence of epithelium. These findings suggest that, in diastema mesenchyme, restriction of Shh activity is dependent upon the overlying epithelium. This inhibitory activity was demonstrated by the ability of transplanted diastema epithelium to downregulate Ptc1 in tooth explants, and for isolated diastema mesenchyme to express Ptc1. A candidate inhibitor in diastema mesenchyme is the glycosylphosphatidylinositol-linked membrane glycoprotein Gas1. Gas1 is normally expressed throughout mandibular arch mesenchyme; however, in the absence of epithelium this expression was downregulated specifically in the diastema where ectopic Shh protein was identified. Although Shh signalling has no effect upon Gas1 expression in mandibular arch mesenchyme, overexpression of Gas1 results in downregulation of ectopic Ptc1. Therefore, control of the position of tooth initiation in the mandibular arch involves a combination of Shh signalling at sites where teeth are required and antagonism in regions destined to remain edentulous.