Rubbini Davide, Robert-Moreno Àlex, Hoijman Esteban, Alsina Berta
Laboratory of Developmental Biology, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, 08003 Barcelona, Spain.
Laboratory of Developmental Biology, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, 08003 Barcelona, Spain
J Neurosci. 2015 Nov 25;35(47):15752-66. doi: 10.1523/JNEUROSCI.1099-15.2015.
During development, otic sensory progenitors give rise to hair cells and supporting cells. In mammalian adults, differentiated and quiescent sensory cells are unable to generate new hair cells when these are lost due to various insults, leading to irreversible hearing loss. Retinoic acid (RA) has strong regenerative capacity in several organs, but its role in hair cell regeneration is unknown. Here, we use genetic and pharmacological inhibition to show that the RA pathway is required for hair cell regeneration in zebrafish. When regeneration is induced by laser ablation in the inner ear or by neomycin treatment in the lateral line, we observe rapid activation of several components of the RA pathway, with dynamics that position RA signaling upstream of other signaling pathways. We demonstrate that blockade of the RA pathway impairs cell proliferation of supporting cells in the inner ear and lateral line. Moreover, in neuromast, RA pathway regulates the transcription of p27(kip) and sox2 in supporting cells but not fgf3. Finally, genetic cell-lineage tracing using Kaede photoconversion demonstrates that de novo hair cells derive from FGF-active supporting cells. Our findings reveal that RA has a pivotal role in zebrafish hair cell regeneration by inducing supporting cell proliferation, and shed light on the underlying transcriptional mechanisms involved. This signaling pathway might be a promising approach for hearing recovery.
Hair cells are the specialized mechanosensory cells of the inner ear that capture auditory and balance sensory input. Hair cells die after acoustic trauma, ototoxic drugs or aging diseases, leading to progressive hearing loss. Mammals, in contrast to zebrafish, lack the ability to regenerate hair cells. Here, we find that retinoic acid (RA) pathway is required for hair cell regeneration in vivo in the zebrafish inner ear and lateral line. RA pathway is activated very early upon hair cell loss, promotes cell proliferation of progenitor cells, and regulates two key genes, p27(kip) and sox2. Our results position RA as an essential signal for hair cell regeneration with relevance in future regenerative strategies in mammals.
在发育过程中，耳感觉祖细胞产生毛细胞和支持细胞。在成年哺乳动物中，当这些细胞因各种损伤而丢失时，已分化且静止的感觉细胞无法产生新的毛细胞，导致不可逆的听力损失。视黄酸（RA）在多个器官中具有强大的再生能力，但其在毛细胞再生中的作用尚不清楚。在这里，我们使用基因和药理学抑制方法表明，RA信号通路是斑马鱼毛细胞再生所必需的。当通过内耳激光消融或侧线新霉素处理诱导再生时，我们观察到RA信号通路的几个成分迅速激活，其动力学将RA信号置于其他信号通路的上游。我们证明，阻断RA信号通路会损害内耳和侧线中支持细胞的细胞增殖。此外，在神经丘中，RA信号通路调节支持细胞中p27（kip）和sox2的转录，但不调节fgf3。最后，使用Kaede光转化进行的遗传细胞谱系追踪表明，新生毛细胞源自FGF活性支持细胞。我们的研究结果表明，RA通过诱导支持细胞增殖在斑马鱼毛细胞再生中起关键作用，并揭示了其潜在的转录机制。这条信号通路可能是恢复听力的一种有前途的方法。
毛细胞是内耳中捕获听觉和平衡感觉输入的特殊机械感觉细胞。毛细胞在声学创伤、耳毒性药物或衰老疾病后死亡，导致进行性听力损失。与斑马鱼不同，哺乳动物缺乏再生毛细胞的能力。在这里，我们发现视黄酸（RA）信号通路是斑马鱼内耳和侧线中毛细胞体内再生所必需的。毛细胞损失后，RA信号通路很早就被激活，促进祖细胞的细胞增殖，并调节两个关键基因p27（kip）和sox2。我们的结果将RA定位为毛细胞再生的必需信号，与未来哺乳动物的再生策略相关。
