Yamaguchi Masahiro, Tonou-Fujimori Noriko, Komori Atsuko, Maeda Ryu, Nojima Yasuhiro, Li Haichang, Okamoto Hitoshi, Masai Ichiro
Masai Initiative Research Unit, RIKEN (The Institute of Physical and Chemical Research.
Development. 2005 Jul;132(13):3027-43. doi: 10.1242/dev.01881.
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.
在发育中的脊椎动物视网膜中，祖细胞最初进行增殖，但当神经元分化发生时，它们开始产生有丝分裂后神经元。然而，决定视网膜祖细胞是继续增殖还是退出细胞周期并进行分化的机制在很大程度上尚不清楚。在此，我们报告组蛋白去乙酰化酶1（Hdac1）是斑马鱼视网膜从增殖向分化转变所必需的。我们分离出一种斑马鱼突变体，即升降突变体（add），其中视网膜细胞无法分化为神经元和神经胶质细胞，而是继续增殖。add基因的克隆显示它编码Hdac1。此外，分化细胞数量与增殖细胞数量的比例与Hdac活性成比例增加，这表明Hdac蛋白调节斑马鱼视网膜神经发生的关键步骤。经典的Wnt信号通路促进斑马鱼视网膜细胞的增殖，而Notch信号通路通过激活神经源性抑制剂毛状/分裂增强子（Hes）来抑制神经元分化。我们发现Wnt和Notch/Hes通路在add突变体视网膜中均被激活。add突变体视网膜中的细胞周期进程和Hes表达的上调可分别通过阻断Wnt和Notch信号通路来抑制。这些数据表明，Hdac1拮抗这些通路以促进斑马鱼视网膜中的细胞周期退出和随后的神经发生。综上所述，这些数据表明Hdac1作为一个双重开关，抑制斑马鱼视网膜中的细胞周期进程和神经发生抑制。
