Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.
J Cell Physiol. 2010 Jun;223(3):601-9. doi: 10.1002/jcp.22046.
Coordinated differentiation of the ameloblast cell layer is essential to enamel matrix protein deposition and subsequent mineralization. It has been hypothesized that this process is governed by Cx43-based gap junctional intercellular communication as oculodentodigital dysplasia (ODDD) patients harboring autosomal-dominant mutations in Cx43 exhibit enamel defects typically resulting in early adulthood tooth loss. To assess the role of Cx43 in tooth development we employ a mouse model of ODDD that harbors a G60S Cx43 mutant, Gja1(Jrt)/+, and appears to exhibit tooth abnormalities that mimic the human disease. We found that total Cx43 plaques at all stages of ameloblast differentiation, as well as within the supporting cell layers, were greatly reduced in Gja1(Jrt)/+ incisors compared to wild-type littermate controls. To characterize the Gja1(Jrt)/+ mouse tooth phenotype, mice were sacrificed prior to tooth eruption (postnatal day 7), weaning (postnatal day 21), and adulthood (2 months postnatal). A severely disorganized Gja1(Jrt)/+ mouse ameloblast layer and abnormal accumulation of amelogenin were observed at stages when the cells were active in secretion and mineralization. Differences in enamel thickness became more apparent after tooth eruption and incisor exposure to the oral cavity suggesting that enamel integrity is compromised, leading to rapid erosion. Additional analysis of incisors from mutant mice revealed that they were longer with a thicker dentin layer than their wild-type littermates, which may reflect a mechanical stress response to the depleted enamel layer. Together, these data show that reduced levels of Cx43 gap junctions result in ameloblast dysregulation, enamel hypoplasia, and secondary tissue responses.
细胞层的协调分化对于釉基质蛋白的沉积和随后的矿化至关重要。有人假设，这个过程受 Cx43 为基础的缝隙连接细胞间通讯控制，因为患有常染色体显性突变的眼-牙-指发育不良（ODDD）患者表现出典型的釉质缺陷，通常导致成年早期牙齿缺失。为了评估 Cx43 在牙齿发育中的作用，我们使用了一种 ODDD 的小鼠模型，该模型携带 G60S Cx43 突变体 Gja1(Jrt)/+，并且似乎表现出类似于人类疾病的牙齿异常。我们发现，在 Gja1(Jrt)/+切牙的所有成釉细胞分化阶段以及支持细胞层中，总 Cx43 斑都明显减少，与野生型同窝仔鼠对照相比。为了表征 Gja1(Jrt)/+小鼠的牙齿表型，我们在牙齿萌出前（出生后 7 天）、断奶时（出生后 21 天）和成年后（出生后 2 个月）处死小鼠。在细胞活跃于分泌和矿化的阶段，观察到 Gja1(Jrt)/+ 小鼠的成釉细胞层严重紊乱和釉原蛋白异常积累。在牙齿萌出后，以及切牙暴露于口腔中后，牙釉质厚度的差异变得更加明显，这表明牙釉质完整性受损，导致快速侵蚀。对突变小鼠切牙的进一步分析表明，它们比野生型同窝仔鼠更长，牙本质层更厚，这可能反映了对耗尽的牙釉质层的机械应激反应。总之，这些数据表明，Cx43 缝隙连接的水平降低导致成釉细胞失调、釉质发育不全和继发组织反应。
