Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration.
Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration.
复制标题
斑马鱼神经丘毛细胞再生需要 Myc 和 Fgf
DOI：
10.1371/journal.pone.0157768
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Chen ZY
中科院分区：
文献类型：
--
作者：
Lee SG;Huang M;Obholzer ND;Sun S;Li W;Petrillo M;Dai P;Zhou Y;Cotanche DA;Megason SG;Li H;Chen ZY
与哺乳动物不同，非哺乳类脊椎动物内耳可以自发再生感觉细胞，也可以在毛细胞丧失后通过诱导再生毛细胞，从而恢复听力。人们对再生的机制知之甚少。通过对鸡模型的基因芯片分析，我们发现鸡毛细胞的再生涉及到增殖基因的激活和分化基因的下调。在鸡毛细胞再生过程中，MYC和成纤维细胞生长因子均被激活。利用斑马鱼侧线神经肥大毛细胞再生模型，我们发现Myc或成纤维细胞生长因子的特异性抑制抑制了毛细胞再生，表明这两条途径在这一过程中都是必不可少的。在再生过程中Myc的快速上调和Fgf的延迟激活，提示Myc在增殖中起作用，而Fgf在分化中起作用。FGFR1a在神经肥大的背腹模式与毛细胞前体的分布重叠。通过激光消融，我们发现FGFRA1a阳性的支持细胞可能是直接产生新毛细胞的毛细胞前体；而前后FGFR1a阴性的支持细胞具有更高的增殖能力，可能作为更原始的前体细胞来补充毛细胞丢失后丢失的前体细胞。因此，Fgfr1a可能标记不同的支持细胞亚型，在更新、增殖和毛细胞再生方面具有不同的能力。C-myc和成纤维细胞生长因子通路的调控可用于哺乳动物毛细胞再生。
Unlike mammals, the non-mammalian vertebrate inner ear can regenerate the sensory cells, hair cells, either spontaneously or through induction after hair cell loss, leading to hearing recovery. The mechanisms underlying the regeneration are poorly understood. By microarray analysis on a chick model, we show that chick hair cell regeneration involves the activation of proliferation genes and downregulation of differentiation genes. Both MYC and FGF are activated in chick hair cell regeneration. Using a zebrafish lateral line neuromast hair cell regeneration model, we show that the specific inhibition of Myc or Fgf suppresses hair cell regeneration, demonstrating that both pathways are essential to the process. Rapid upregulation of Myc and delayed Fgf activation during regeneration suggest a role of Myc in proliferation and Fgf in differentiation. The dorsal-ventral pattern of fgfr1a in the neuromasts overlaps with the distribution of hair cell precursors. By laser ablation, we show that the fgfr1a-positive supporting cells are likely the hair cell precursors that directly give rise to new hair cells; whereas the anterior-posterior fgfr1a-negative supporting cells have heightened proliferation capacity, likely to serve as more primitive progenitor cells to replenish lost precursors after hair cell loss. Thus fgfr1a is likely to mark compartmentalized supporting cell subtypes with different capacities in renewal proliferation and hair cell regeneration. Manipulation of c-MYC and FGF pathways could be explored for mammalian hair cell regeneration.