失去了Sirt6激活了Got1并通过异常的激活糖解促进了口腔裂
Xiaotong Wang1, Xige Zhao1, Xiaoyu Zheng1
1Laboratory of Orofacial Development, Laboratory of Molecular Signaling and Stem Cells Therapy, Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Re-generation and Function Reconstruction, Capital Medical University School of Stomatology, Fanjiacun Road No.9, Beijing, 100070, China.
Cell death & disease
|March 6, 2025
概括
宫口发育中的Sirtuin6 (SIRT6) 缺乏会抑制骨的形成,导致宫口裂. 这通过增加谷氨胺氧酸转胺酶1 (GOT1) 和改变细胞信号通路而发生,突出显示SIRT6.
科学领域:
- 发展生物学 发展生物学
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 口腔裂 (CP) 是一种常见的先天性面形,具有复杂的遗传和环境原因.
- 赛尔图因6 (SIRT6) 突变与面异常有关,但其在 palatal 发育中的具体作用尚不清楚.
- 了解 palatogenesis 背后的分子机制对于解决 CP 病因学至关重要.
研究的目的:
- 通过检查其在Wnt1表达细胞系中的无活化来研究Sirtuin6 (SIRT6) 在 palatogenesis中的作用.
- 阐明SIRT6缺乏影响骨的分子机制,并导致裂.
- 确定关键的分子参与者和涉及SIRT6介导口腔发生的途径.
主要方法:
- 产生的Sirtuin6条件淘汰赛 (Sirt6 cKO) 小鼠,特别是在Wnt1表达细胞中.
- 分析了Sirt6缺乏胚胎的 palatal骨质生成,细胞增殖和分化.
- 研究了谷氨胺氧酸转胺酶1 (GOT1),糖解和相关信号通路 (LDHA,TGFBR1,BMP2) 的作用.
- 评估了环境因素的影响,如视网膜酸 (RA) 和组蛋白修饰剂的参与 (TIP60,P300).
主要成果:
- 在 palatal mesenchyme 细胞 (MEPM) 中的 Sirtuin6 缺乏抑制了骨质生成,导致 palatal 裂.
- 通过脱乙烯化抑制,SIRT6缺乏可以提高谷氨胺氧酸转胺酶1 (GOT1) 和糖解的调节.
- 通过GOT1-LDHA通路调解增加了MEPM细胞增殖 (通过TGFBR1) 并抑制了骨质生成分化 (通过BMP2).
- 环境干扰,如网膜酸加剧了CP的发生.
- GOT1由TIP60,而不是P300的基因组乙化是由Sirt6缺乏引起的.
- 对GOT1的抑制部分挽救了裂口 palatal 现型.
结论:
- 赛尔图因6在调节 palatal 骨质生成和预防 palatal 裂方面发挥着至关重要的作用.
- 缺少SIRT6通过调节GOT1并改变参与增殖和分化的关键细胞信号通路,促进了口腔裂.
- GOT1被确定为Sirt6介导机制的关键驱动因素,是裂口发育的基础.
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