Beane Wendy S, Morokuma Junji, Adams Dany S, Levin Michael
Biology Department and Tufts Center for Regenerative and Developmental Biology, Tufts University, Medford, MA 02155-4243, USA.
Chem Biol. 2011 Jan 28;18(1):77-89. doi: 10.1016/j.chembiol.2010.11.012.
Biophysical signaling is required for both embryonic polarity and regenerative outgrowth. Exploiting endogenous ion transport for regenerative therapies will require direct regulation of membrane voltage. Here, we develop a pharmacological method to target ion transporters, uncovering a role for membrane voltage as a key regulator of anterior polarity in regenerating planaria. Utilizing the highly specific inhibitor, SCH-28080, our data reveal that H(+),K(+)-ATPase-mediated membrane depolarization is essential for anterior gene expression and brain induction. H(+),K(+)-ATPase-independent manipulation of membrane potential with ivermectin confirms that depolarization drives head formation, even at posterior-facing wounds. Using this chemical genetics approach, we demonstrate that membrane voltage controls head-versus-tail identity during planarian regeneration. Our data suggest well-characterized drugs (already approved for human use) might be exploited to control adult stem cell-driven pattern formation during the regeneration of complex structures.
生物物理信号传导对于胚胎极性和再生生长都是必需的。利用内源性离子转运进行再生治疗将需要直接调节膜电压。在这里，我们开发了一种靶向离子转运体的药理学方法，揭示了膜电压作为再生涡虫前极性关键调节因子的作用。利用高度特异性抑制剂SCH-28080，我们的数据表明，H(+)，K(+)-ATP酶介导的膜去极化对于前部基因表达和脑诱导至关重要。用伊维菌素对膜电位进行H(+)，K(+)-ATP酶非依赖性操作证实，去极化驱动头部形成，即使在面向后部的伤口处也是如此。使用这种化学遗传学方法，我们证明了膜电压在涡虫再生过程中控制头部与尾部的身份。我们的数据表明，特征明确的药物（已批准用于人类）可能被用于控制复杂结构再生过程中成年干细胞驱动的模式形成。
