Development and Regeneration Laboratory, Department of Zoology, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand.
Mech Dev. 2012 Sep-Dec;129(9-12):208-18. doi: 10.1016/j.mod.2012.08.001. Epub 2012 Aug 26.
Amphibians such as Xenopus laevis and Ambystoma mexicanum are capable of whole structure regeneration. However, transcriptional control over these events is not well understood. Here, we investigate the role of histone deacetylase (HDAC) enzymes in regeneration using HDAC inhibitors. The class I/II HDAC inhibitor valproic acid (VPA) inhibits tail regeneration in embryos of the anuran amphibian Xenopus laevis, confirming a recent report by others (Tseng et al., 2011). This inhibition correlates with a sixfold reduction in endogenous HDAC activity. VPA also inhibited tail regeneration in post-refractory stage Xenopus larvae and larvae of the urodele A. mexicanum (axolotl). Furthermore, Xenopus limb regeneration was also significantly impaired by post-amputation treatment with VPA, suggesting a general requirement for HDAC activity in the process of appendage regeneration in amphibians. The most potent inhibition of tail regeneration was observed following treatment with VPA during the wound healing, pre-blastema phase. A second HDAC inhibitor, sodium butyrate, was also shown to inhibit tail regeneration. While both VPA and sodium butyrate are reported to block sodium channel function as well as HDACs, regeneration was not inhibited by valpromide, an analogue of VPA that lacks HDAC inhibition but retains sodium channel blocking activity. Finally, although VPA is a known teratogen, we show that neither tailbud nor limb bud development are affected by exposure to this compound. We conclude that histone deacetylation is specifically required for the earliest events in appendage regeneration in amphibians, and suggest that this may act as a switch to trigger re-expression of developmental genes.
爪蟾（Xenopus laevis）和墨西哥钝口螈（Ambystoma mexicanum）等两栖动物能够进行整体结构再生。然而，人们对这些事件的转录控制还了解甚少。在这里，我们使用组蛋白去乙酰化酶（HDAC）抑制剂研究 HDAC 酶在再生中的作用。I/II 类 HDAC 抑制剂丙戊酸（VPA）抑制无尾两栖动物爪蟾（Xenopus laevis）胚胎的尾巴再生，证实了最近其他人的一份报告（Tseng 等人，2011 年）。这种抑制作用与内源性 HDAC 活性降低六倍相关。VPA 还抑制了后refractory 期的 Xenopus 幼虫和有尾目两栖动物 A. mexicanum（axolotl）的尾巴再生。此外，VPA 对 Xenopus 肢体再生的影响也非常显著，表明 HDAC 活性在两栖动物附肢再生过程中普遍需要。在创伤愈合、前芽基期用 VPA 进行治疗后，观察到尾巴再生的抑制最为明显。另一种 HDAC 抑制剂丁酸钠也被证明能抑制尾巴再生。虽然 VPA 和丁酸钠都被报道能阻断钠通道功能和 HDAC，但缺乏 HDAC 抑制但保留钠通道阻断活性的 VPA 类似物 valpromide 并没有抑制再生。最后，尽管 VPA 是一种已知的致畸剂，但我们表明暴露于该化合物不会影响尾巴芽或肢体芽的发育。我们得出结论，组蛋白去乙酰化是两栖动物附肢再生早期事件所必需的，并且表明这可能作为触发发育基因重新表达的开关。
