Departments of Pathology & Laboratory Medicine and Biology, Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Oral & Craniofacial Health Sciences, The University of North Carolina School of Dentistry, Chapel Hill, NC 27599, USA.
Development. 2020 Jul 13;147(21):dev189241. doi: 10.1242/dev.189241.
Cleft palate (CP), one of the most common congenital conditions, arises from failures in secondary palatogenesis during embryonic development. Several human genetic syndromes featuring CP and ectodermal dysplasia have been linked to mutations in genes regulating cell-cell adhesion, yet mouse models have largely failed to recapitulate these findings. Here, we use lentiviral-mediated genetic approaches in mice to provide the first direct evidence that the nectin-afadin axis is essential for proper palate shelf elevation and fusion. Using this technique, we demonstrate that palatal epithelial conditional loss of afadin () - an obligate nectin- and actin-binding protein - induces a high penetrance of CP, not observed when is targeted later using We implicate and as being crucially involved, as loss of either induces a low penetrance of mild palate closure defects, while loss of both causes severe CP with a frequency similar to loss. Finally, expression of the human disease mutant causes CP with greater penetrance than loss, suggesting this alteration may drive CP via a dominant interfering mechanism.
腭裂（CP）是最常见的先天性疾病之一，它是胚胎发育过程中二次腭发生失败引起的。一些表现为 CP 和外胚层发育不良的人类遗传综合征与调节细胞-细胞黏附的基因突变有关，但小鼠模型在很大程度上未能重现这些发现。在这里，我们使用慢病毒介导的遗传方法在小鼠中提供了第一个直接证据，证明了 nectin-afadin 轴对于适当的腭突升高和融合是必不可少的。使用这项技术，我们证明了腭上皮细胞条件性缺失 afadin()——一种必需的 nectin 和肌动蛋白结合蛋白——会导致 CP 的高发生率，而当以后使用 靶向缺失时则不会观察到这种情况。我们暗示 和 是至关重要的，因为缺失任何一个都会导致轻度腭裂闭合缺陷的低发生率，而缺失两个则会导致严重的 CP，其发生率与缺失相似。最后，表达人类疾病突变体 会导致 CP 的发生率高于 缺失，这表明这种改变可能通过显性干扰机制导致 CP。
