Neurite outgrowth inhibitor A (Nogo-A) is a major player in neural development and regeneration and the target of clinical trials aiming at promoting the regeneration of the central nervous system upon traumatic and ischemic injury. In this work, we investigated the functions of Nogo-A during tooth development to determine its role in dental physiology and pathology. Using immunohistochemistry and in situ hybridization techniques, we showed that Nogo-A is highly expressed in the developing mouse teeth and, most specifically, in the ameloblasts that are responsible for the formation of enamel. Using both Nogo-A knockout and K14-Cre;Nogo-A fl/fl transgenic mice, we showed that Nogo-A deletion in the dental epithelium leads to the formation of defective enamel. This phenotype is associated with overexpression of a set of specific genes involved in ameloblast differentiation and enamel matrix production, such as amelogenin, ameloblastin and enamelin. By characterising the interactome of Nogo-A in the dental epithelium of wild-type and mutant animals, we found that Nogo-A directly interacts with molecules important for regulating gene expression, and its deletion disturbs their cellular localisation. Furthermore, we demonstrated that inhibition of the intracellular, but not cell-surface, Nogo-A is responsible for gene expression modulation in ameloblasts. Taken together, these results reveal an unexpected function for Nogo-A in tooth enamel formation by regulating gene expression and cytodifferentiation events.

神经突生长抑制剂 A （Nogo-A） 是神经发育和再生的主要参与者，是旨在促进创伤和缺血性损伤后中枢神经系统再生的临床试验目标。在这项工作中，我们研究了 Nogo-A 在牙齿发育过程中的功能，以确定其在牙齿生理学和病理学中的作用。使用免疫组织化学和原位杂交技术，我们表明 Nogo-A 在发育中的小鼠牙齿中高度表达，最具体地说，在负责形成牙釉质的成釉细胞中。同时使用 Nogo-A 敲除和 K14-Cre;Nogo-A fl/fl 转基因小鼠，我们发现牙上皮中的 Nogo-A 缺失导致有缺陷的牙釉质的形成。这种表型与一组参与成釉细胞分化和牙釉质基质产生的特定基因的过表达有关，例如成釉质生成素、成釉细胞素和牙釉质蛋白。通过表征野生型和突变型动物齿上皮中 Nogo-A 的相互作用组，我们发现 Nogo-A 直接与调节基因表达的重要分子相互作用，其缺失会干扰它们的细胞定位。此外，我们证明抑制细胞内而不是细胞表面 Nogo-A 负责成釉细胞中的基因表达调节。综上所述，这些结果揭示了 Nogo-A 通过调节基因表达和细胞分化事件在牙釉质形成中的意想不到的功能。