Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Dis Model Mech. 2023 Oct 1;16(10). doi: 10.1242/dmm.050085. Epub 2023 Oct 17.
Cleft palate has a multifactorial etiology. In palatal fusion, the contacting medial edge epithelium (MEE) forms the epithelial seam, which is subsequently removed with the reduction of p63. Failure in this process results in a cleft palate. We herein report the involvement of janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in palatal fusion and that folic acid rescues the fusing defect by reactivating JAK2/STAT3. In closure of bilateral palatal shelves, STAT3 phosphorylation was activated at the fusing MEE and mesenchyme underlying the MEE. JAK2 inhibition by AG490 inhibited STAT3 phosphorylation and resulted in palatal fusion failure without removal of the epithelial seam, in which p63 and keratin 17 (K17) periderm markers were retained. Folic acid application restored STAT3 phosphorylation in AG490-treated palatal explants and rescued the fusion defect, in which the p63- and K17-positive epithelial seam were removed. The AG490-induced palatal defect was also rescued in p63 haploinsufficient explants. These findings suggest that JAK2/STAT3 signaling is involved in palatal fusion by suppressing p63 expression in MEE and that folate restores the fusion defect by reactivating JAK2/STAT3.
腭裂具有多因素病因。在腭融合中，接触的内侧缘上皮（MEE）形成上皮缝线，随后随着 p63 的减少而被去除。如果这个过程失败，就会导致腭裂。本文报道了 Janus 激酶 2（JAK2）/信号转导和转录激活因子 3（STAT3）信号在腭融合中的作用，以及叶酸通过重新激活 JAK2/STAT3 来挽救融合缺陷。在双侧腭突闭合过程中，STAT3 磷酸化在融合的 MEE 和 MEE 下的间充质中被激活。AG490 抑制 JAK2 可抑制 STAT3 磷酸化，导致腭融合失败，而上皮缝线未被去除，其中 p63 和角蛋白 17（K17）表皮标志物被保留。叶酸在 AG490 处理的腭突外植体中恢复了 STAT3 磷酸化，挽救了融合缺陷，其中 p63 和 K17 阳性的上皮缝线被去除。AG490 诱导的腭裂缺陷也在 p63 杂合不足的外植体中得到挽救。这些发现表明，JAK2/STAT3 信号通过抑制 MEE 中的 p63 表达参与腭融合，而叶酸通过重新激活 JAK2/STAT3 来挽救融合缺陷。
