Identification of modulators of hair cell regeneration in the zebrafish lateral line.
Identification of modulators of hair cell regeneration in the zebrafish lateral line.
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DOI：
10.1523/jneurosci.3905-11.2012
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发表时间：
2012-03-07
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影响因子：
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通讯作者：
Rubel EW
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文献类型：
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作者：
Namdaran P;Reinhart KE;Owens KN;Raible DW;Rubel EW
斑马鱼侧线的外部位置使其成为研究机械感觉毛细胞再生的有力模型。我们已经开发了一种化学筛选，以确定FDA批准的药物和生物活性化合物，调节斑马鱼毛细胞再生。在评估的1，680种化合物中，我们鉴定了2种再生增强剂和6种再生抑制剂。这两种增强剂，地塞米松和泼尼松龙，是合成的糖皮质激素，在再生过程中增强毛细胞数量，并在没有损伤的情况下诱导毛细胞增加。BrdU分析证实，额外的毛细胞来自有丝分裂活动。我们发现，地塞米松和泼尼松龙，像其他糖皮质激素，抑制斑马鱼尾鳍再生，表明毛细胞再生发生了一个明显不同的过程。对再生抑制剂的进一步分析显示，六种中的两种，氟苯达唑和拓扑替康，通过阻止毛细胞前体的增殖来显著抑制毛细胞再生。氟苯达唑可能通过干扰正常微管活性而使支持细胞分裂停止在M期。拓扑异构酶抑制剂Topotecan可杀死毛细胞和增殖的毛细胞前体。第三种抑制剂，氟维司群，通过减少支持细胞增殖适度延迟毛细胞再生。我们的观察，毛细胞不再生时，支持细胞增殖受阻证实了以前的观察，细胞分裂是毛细胞再生后，新霉素治疗斑马鱼的主要途径。
The external location of the zebrafish lateral line makes it a powerful model for studying mechanosensory hair cell regeneration. We have developed a chemical screen to identify FDA-approved drugs and biologically active compounds that modulate hair cell regeneration in zebrafish. Of the 1,680 compounds evaluated, we identified 2 enhancers and 6 inhibitors of regeneration. The two enhancers, dexamethasone and prednisolone, are synthetic glucocorticoids that potentiated hair cell numbers during regeneration and also induced hair cell addition in the absence of damage. BrdU analysis confirmed that the extra hair cells arose from mitotic activity. We found that dexamethasone and prednisolone, like other glucocorticoids, suppress zebrafish caudal fin regeneration, indicating that hair cell regeneration occurs by a distinctly different process. Further analyses of the regeneration inhibitors revealed that two of the six, flubendazole and topotecan, significantly suppress hair cell regeneration by preventing proliferation of hair cell precursors. Flubendazole halted support cell division in M-phase, possibly by interfering with normal microtubule activity. Topotecan, a topoisomerase inhibitor, killed both hair cells and proliferating hair cell precursors. A third inhibitor, fulvestrant, moderately delays hair cell regeneration by reducing support cell proliferation. Our observation that hair cells do not regenerate when support cell proliferation is impeded confirms previous observations that cell division is the primary route for hair cell regeneration after neomycin treatment in zebrafish.