Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways
Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways
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DOI：
10.1242/dev.01881
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发表时间：
2005-07-01
期刊：
影响因子：
4.6
通讯作者：
Masai, I
中科院分区：
文献类型：
--
作者：
Yamaguchi, M;Tonou-Fujimori, N;Masai, I
在发育中的脊椎动物视网膜中，祖细胞最初增殖，但当神经元分化发生时，祖细胞开始产生有丝分裂后神经元。然而，决定视网膜祖细胞是否继续增殖或退出细胞周期和分化的机制在很大程度上是未知的。在这里，我们报告，组蛋白脱乙酰酶1（Hdac 1）是必需的开关从增殖到分化的斑马鱼视网膜。我们分离出一种斑马鱼突变体，即上升和下降（add），视网膜细胞不能分化成神经元和神经胶质细胞，而是继续增殖。add基因的克隆表明它编码Hdac 1。此外，分化细胞的数量与增殖细胞的数量之比与HSP 70活性成比例地增加，表明HSP 70蛋白调节斑马鱼视网膜神经发生的关键步骤。经典Wnt信号促进斑马鱼视网膜细胞的增殖，Notch信号通过激活神经原性抑制剂Hairy/Enhancer-of-split（Hes）抑制神经元分化。我们发现Wnt和Notch/Hes通路在add突变体视网膜中都被激活。阻断Wnt和Notch信号通路可分别抑制细胞周期进程和Hes表达上调。这些数据表明，Hdac 1拮抗这些途径，以促进细胞周期退出和随后的神经发生在斑马鱼视网膜。总而言之，这些数据表明Hdac 1具有双重开关的功能，可以抑制细胞周期进程和抑制斑马鱼视网膜的神经发生。
In the developing vertebrate retina, progenitor cells initially proliferate but begin to produce postmitotic neurons when neuronal differentiation occurs. However, the mechanism that determines whether retinal progenitor cells continue to proliferate or exit from the cell cycle and differentiate is largely unknown. Here, we report that histone deacetylase 1 (Hdac1) is required for the switch from proliferation to differentiation in the zebrafish retina. We isolated a zebrafish mutant, ascending and descending (add), in which retinal cells fail to differentiate into neurons and glial cells but instead continue to proliferate. The cloning of the add gene revealed that it encodes Hdac1. Furthermore, the ratio of the number of differentiating cells to that of proliferating cells increases in proportion to Hdac activity, suggesting that Hdac proteins regulate a crucial step of retinal neurogenesis in zebrafish. Canonical Wnt signaling promotes the proliferation of retinal cells in zebrafish, and Notch signaling inhibits neuronal differentiation through the activation of a neurogenic inhibitor, Hairy/Enhancer-of-split (Hes). We found that both the Wnt and Notch/Hes pathways are activated in the add mutant retina. The cell-cycle progression and the upregulation of Hes expression in the add mutant retina can be inhibited by the blockade of Wnt and Notch signaling, respectively. These data suggest that Hdac1 antagonizes these pathways to promote cell-cycle exit and the subsequent neurogenesis in zebrafish retina. Taken together, these data suggest that Hdac1 functions as a dual switch that suppresses both cell-cycle progression and inhibition of neurogenesis in the zebrafish retina.