FGF9 通过 Wnt/β-连环蛋白/TCF7L2 通路促进腭隆起中 HAS2 的表达。
FGF9 Promotes Expression of HAS2 in Palatal Elevation via the Wnt/β-Catenin/TCF7L2 Pathway.
机构信息
Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, China.
Department of Stomatology, Huadong Hospital, Fudan University, Shanghai 200040, China.
出版信息
Biomolecules. 2022 Nov 4;12(11):1639. doi: 10.3390/biom12111639.
BACKGROUND
mutation was found in cleft palate patients. Our previous study indicated that promotes timely elevation of palate by regulating hyaluronic acid (HA) accumulation at embryonic day 13.5 (E13.5). HA is synthesized by hyaluronic acid synthases (HAS) isoforms 1, 2, or 3. However, how FGF9 regulates HA in palatogenesis is still unclear.
METHODS
Using Ddx4-Cre mice, we generated the mouse model (with exon 2 deletion). Immunohistochemistry was used to detect the location and expression of HAS2 in WT and the palate at E13.5. We also predicted the association between and within the developing palate by performing a bioinformatics analysis. The expression of β-catenin, HAS2, and TCF7L2 were verified by Western blotting after knockout of . Rescue experiments were performed by ELISA in vitro.
RESULTS
mice exhibited 100% penetrance of the cleft palate. A knockout of confirmed that HAS2 and TCF7L2 expression was positively correlated with FGF9. TCF7L2 binds to the promoter, exhibiting the high specificity predicted by JASPAR. Additionally, increased HA expression by BML-284, TCF-dependent agonist, was blocked in palate because of the significant decline in TCF7L2 expression.
CONCLUSIONS
FGF9 promotes HAS2 expression via Wnt/β-catenin/TCF7L2 pathway with TCF7L2 activating transcription of in the palate.
背景
在腭裂患者中发现了突变。我们之前的研究表明，通过调节胚胎第 13.5 天（E13.5）的透明质酸（HA）积累，促进腭的及时升高。HA 是由透明质酸合酶（HAS）同工型 1、2 或 3 合成的。然而，FGF9 如何在腭发育中调节 HA 仍不清楚。
方法
我们使用 Ddx4-Cre 小鼠，生成了（外显子 2 缺失）小鼠模型。免疫组织化学用于检测 WT 和 E13.5 时的 HAS2 在 和 腭中的位置和表达。我们还通过进行生物信息学分析来预测 在发育中的腭之间的关联。β-catenin、HAS2 和 TCF7L2 的表达在 缺失后通过 Western blot 进行验证。体外进行 ELISA 进行挽救实验。
结果
小鼠表现出 100%的腭裂穿透率。敲除 证实 HAS2 和 TCF7L2 的表达与 FGF9 呈正相关。TCF7L2 与 启动子结合，表现出 JASPAR 预测的高特异性。此外，由于 TCF7L2 表达的显著下降，BML-284（TCF 依赖性激动剂）增加 HA 表达的作用在 腭裂中被阻断。
结论
FGF9 通过 Wnt/β-catenin/TCF7L2 途径促进 HAS2 表达，其中 TCF7L2 激活 转录在腭中。
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