Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IA, USA.
Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, USA.
J Dent Res. 2020 Nov;99(12):1397-1405. doi: 10.1177/0022034520939013. Epub 2020 Jul 17.
In humans, ankyloglossia and cleft palate are common congenital craniofacial anomalies, and these are regulated by a complex gene regulatory network. Understanding the genetic underpinnings of ankyloglossia and cleft palate will be an important step toward rational treatment of these complex anomalies. We inactivated the Sry (sex-determining region Y)-box 2 () gene in the developing oral epithelium, including the periderm, a transient structure that prevents abnormal oral adhesions during development. This resulted in ankyloglossia and cleft palate with 100% penetrance in embryos examined after embryonic day 14.5. In conditional knockout embryos, the oral epithelium failed to differentiate, as demonstrated by the lack of keratin 6, a marker of the periderm. Further examination revealed that the adhesion of the tongue and mandible expressed the epithelial markers and . The expanded epithelia are Sox9-, Pitx2-, and Tbx1-positive cells, which are markers of the dental epithelium; thus, the dental epithelium contributes to the development of oral adhesions. Furthermore, we found that is required for palatal shelf extension, as well as for the formation of palatal rugae, which are signaling centers that regulate palatogenesis. In conclusion, the deletion of in oral epithelium disrupts palatal shelf extension, palatal rugae formation, tooth development, and periderm formation. The periderm is required to inhibit oral adhesions and ankyloglossia, which is regulated by . In addition, oral adhesions occur through an expanded dental epithelial layer that inhibits epithelial invagination and incisor development. This process may contribute to dental anomalies due to ankyloglossia.
在人类中，舌系带过短和腭裂是常见的先天性颅面畸形，这些畸形受复杂的基因调控网络调控。了解舌系带过短和腭裂的遗传基础将是合理治疗这些复杂畸形的重要步骤。我们在发育中的口腔上皮细胞中使 Sry（性别决定区 Y）框 2 () 基因失活，包括暂时的表皮角质形成细胞，它可防止发育过程中的异常口腔粘连。这导致在胚胎第 14.5 天以后检查的胚胎中舌系带过短和腭裂的发生率为 100%。在条件性敲除胚胎中，口腔上皮细胞不能分化，如缺乏角蛋白 6（表皮角质形成细胞的标志物）所证明的那样。进一步检查表明，舌和下颌的粘连表达上皮标志物 和 。扩张的上皮细胞 Sox9、Pitx2 和 Tbx1 阳性细胞，是牙上皮的标志物；因此，牙上皮有助于口腔粘连的发育。此外，我们发现 对于腭突的延伸以及腭皱襞的形成是必需的，腭皱襞是调节腭发育的信号中心。总之，口腔上皮细胞中 缺失会破坏腭突的延伸、腭皱襞的形成、牙齿的发育和表皮角质形成细胞的形成。表皮角质形成细胞是抑制口腔粘连和舌系带过短所必需的，其由 调节。此外，口腔粘连通过抑制上皮内陷和切牙发育的扩张牙上皮层发生。这个过程可能由于舌系带过短导致牙齿畸形。
