Dentin Dysplasia in Notum Knockout Mice
Dentin Dysplasia in Notum Knockout Mice
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DOI：
10.1177/0300985815626778
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发表时间：
2016-07-01
影响因子：
2.4
通讯作者：
Brommage, R.
中科院分区：
文献类型：
--
作者：
Vogel, P.;Read, R. W.;Brommage, R.
分泌的WNT蛋白控制许多组织中的细胞分化和增殖，并且NOTUM是一种分泌酶，其通过去除对其活性至关重要的棕榈油酸酯部分来调节WNT形态发生剂。为了更好地了解这种酶在发育中的作用，作者通过Notum基因的靶向插入破坏产生了Notum缺陷小鼠。作者发现了NOTUM在牙本质形态发生中的关键作用，表明WNT活性增加可以破坏切牙和磨牙中的成牙本质细胞分化和定向。虽然Notum（-/-）小鼠的磨牙具有正常形状的牙冠和正常的套牙本质，但有缺陷的牙冠牙本质导致釉质在咀嚼过程中容易断裂，并使牙齿更容易发生牙髓炎症和坏死。牙本质发育不良和短根导致牙齿过度活动和牙周炎的蔓延，通常进展为根尖周脓肿形成。一些Notum（-/-）小鼠中肾脏发育不全的额外偶然发现表明，NOTUM也在肾脏发育中发挥作用，未诊断的双侧肾脏发育不全最可能是观察到的Notum（-/-）小鼠围产期存活率降低的原因。这些发现支持NOTUM在调节WNT信号通路中的重要作用，WNT信号通路对牙齿和肾脏发育具有多效性作用。
Secreted WNT proteins control cell differentiation and proliferation in many tissues, and NOTUM is a secreted enzyme that modulates WNT morphogens by removing a palmitoleoylate moiety that is essential for their activity. To better understand the role this enzyme in development, the authors produced NOTUM-deficient mice by targeted insertional disruption of the Notum gene. The authors discovered a critical role for NOTUM in dentin morphogenesis suggesting that increased WNT activity can disrupt odontoblast differentiation and orientation in both incisor and molar teeth. Although molars in Notum(-/-) mice had normal-shaped crowns and normal mantle dentin, the defective crown dentin resulted in enamel prone to fracture during mastication and made teeth more susceptible to endodontal inflammation and necrosis. The dentin dysplasia and short roots contributed to tooth hypermobility and to the spread of periodontal inflammation, which often progressed to periapical abscess formation. The additional incidental finding of renal agenesis in some Notum (-/-) mice indicated that NOTUM also has a role in kidney development, with undiagnosed bilateral renal agenesis most likely responsible for the observed decreased perinatal viability of Notum(-/-) mice. The findings support a significant role for NOTUM in modulating WNT signaling pathways that have pleiotropic effects on tooth and kidney development.