Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia
Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia
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DOI：
10.1093/hmg/ddi388
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发表时间：
2005-12-01
影响因子：
3.5
通讯作者：
Peters, H
中科院分区：
文献类型：
--
作者：
Kist, R;Watson, M;Peters, H
牙齿缺失（缺牙和少牙）是人类常见的发育异常，PAX 9的杂合突变最近已被证明是许多家族性非综合征病例的基础。虽然PAX 9单倍不足被认为是潜在的遗传机制，但尚不清楚这如何影响牙齿发育。在这里，我们描述了一种新的，亚型Pax 9突变等位基因（Pax 9（neo））产生的Pax 9野生型mRNA水平下降，并表明这导致小鼠少牙。纯合子Pax 9（neo）突变体（Pax 9（neo/neo））表现出发育不全或缺失的下切牙和第三磨牙，当与无效等位基因Pax 9（lacZ）组合时，复合突变体（Pax 9（neo/lacZ））发展严重形式的少牙。缺失的臼齿在不同的发育阶段被逮捕，后臼齿在早期阶段被逮捕，这表明Pax 9基因剂量的减少会影响整个牙科领域。此外，亚纯型Pax 9突变体在连续生长的门牙的釉质形成中显示出缺陷，而磨牙表现出增加的磨损和修复性牙本质形成。总之，我们得出结论，Pax 9表达水平的变化有一个直接的后果，哺乳动物的牙齿图案和一个最小的Pax 9基因剂量是需要正常的形态发生和分化整个牙齿发育。
Missing teeth (hypodontia and oligodontia) are a common developmental abnormality in humans and heterozygous mutations of PAX9 have recently been shown to underlie a number of familial, non-syndromic cases. Whereas PAX9 haploinsufficiency has been suggested as the underlying genetic mechanism, it is not known how this affects tooth development. Here we describe a novel, hypomorphic Pax9 mutant allele (Pax9(neo)) producing decreased levels of Pax9 wild-type mRNA and show that this causes oligodontia in mice. Homozygous Pax9(neo) mutants (Pax9(neo/neo)) exhibit hypoplastic or missing lower incisors and third molars, and when combined with the null allele Pax9(lacZ), the compound mutants (Pax9(neo/lacZ)) develop severe forms of oligodontia. The missing molars are arrested at different developmental stages and posterior molars are consistently arrested at an earlier stage, suggesting that a reduction of Pax9 gene dosage affects the dental field as a whole. In addition, hypomorphic Pax9 mutants show defects in enamel formation of the continuously growing incisors, whereas molars exhibit increased attrition and reparative dentin formation. Together, we conclude that changes of Pax9 expression levels have a direct consequence for mammalian dental patterning and that a minimal Pax9 gene dosage is required for normal morphogenesis and differentiation throughout tooth development.