N6-methyladenosine (m6A) RNA methylation, one of the most widespread posttranscriptional modifications in eukaryotes, plays crucial roles in various developmental processes. The m6A modification process is catalyzed by a methyltransferase complex that includes Wilms tumor 1-associated protein (WTAP) as a key component. Whether the development of dental enamel is regulated by m6A RNA methylation in mammals remains unclear. Here, we reveal that WTAP is widely expressed from the early stage of tooth development. Specific inactivation of Wtap in mouse enamel epithelium by the Cre/loxp system leads to serious developmental defects in amelogenesis. In Wtap conditional knockout (cKO) mice, we determined that the differentiation of enamel epithelial cells into mature ameloblasts at the early stages of enamel development is affected. Mechanistically, loss of Wtap inhibits the expression of Sonic hedgehog (SHH), which plays an important role in the generation of ameloblasts from stem cells. Together, our findings provide new insights into the functional role of WTAP-mediated m6A methylation in amelogenesis in mammals.

N6-甲基腺苷 (m6A) RNA 甲基化是真核生物中最普遍的转录后修饰之一，在各种发育过程中起着至关重要的作用。m6A 修饰过程由甲基转移酶复合物催化，该复合物包括 Wilms 肿瘤 1 相关蛋白 (WTAP) 作为关键成分。哺乳动物的 m6A RNA 甲基化是否调控牙釉质的发育仍不清楚。在这里，我们发现 WTAP 从牙齿发育的早期阶段就广泛表达。Cre/loxp 系统对小鼠牙釉质上皮细胞中Wtap的特异性灭活会导致釉质形成中出现严重的发育缺陷。在Wtap 中在条件性敲除 (cKO) 小鼠中，我们确定在牙釉质发育的早期阶段，牙釉质上皮细胞向成熟成釉细胞的分化受到影响。从机制上讲， Wtap的缺失会抑制 Sonic hedgehog (SHH) 的表达，SHH 在干细胞生成成釉细胞中起重要作用。总之，我们的研究结果为 WTAP 介导的 m6A 甲基化在哺乳动物釉质形成中的功能作用提供了新的见解。