Direct interaction of geminin and Six3 in eye development
Direct interaction of geminin and Six3 in eye development
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DOI：
10.1038/nature02292
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发表时间：
2004-02-19
期刊：
影响因子：
64.8
通讯作者：
Wittbrodt, J
中科院分区：
文献类型：
--
作者：
Del Bene, F;Tessmar-Raible, K;Wittbrodt, J
脊椎动物的器官发生需要严格控制细胞的增殖和分化。含有同源异型盒的转录因子Six3在视网膜前体细胞的增殖中起着关键作用(1，2)。在酵母双杂交筛选中，我们确定DNA复制抑制因子ginin是Six3的合作伙伴。双黄素通过隔离CDT1(参考文献4，5)抑制细胞周期进展(3)，CDT1是组装复制前复合体的关键成分(6)。在这里，我们展示了Six3有效地与CDT1直接竞争结合到gminin，这揭示了Six3如何在没有转录的情况下促进细胞增殖。与Six3失活(2，7)一样，Geminin基因(Gem；也被称为GMN)在青青中过表达会导致特定的前脑和眼睛缺陷，而Six3可以挽救这些缺陷。相反，宝石的损失(与Six3的收益相同(参考文献1))促进视网膜前体细胞的增殖，导致视泡扩张，显著增强Six3的功能增益表型。我们的数据表明，转录因子Six3和复制起始抑制因子Ginin在脊椎动物早期眼睛发育过程中相互拮抗地控制着增殖和分化之间的平衡。
Organogenesis in vertebrates requires the tight control of cell proliferation and differentiation. The homeobox-containing transcription factor Six3 plays a pivotal role(1,2) in the proliferation of retinal precursor cells. In a yeast two-hybrid screen, we identified the DNA replication-inhibitor geminin as a partner of Six3. Geminin inhibits cell-cycle progression(3) by sequestering Cdt1 (refs 4, 5), the key component for the assembly of the pre-replication complex(6). Here, we show that Six3 efficiently competes with Cdt1 directly to bind to geminin, which reveals how Six3 can promote cell proliferation without transcription. In common with Six3 inactivation(2,7), overexpression of the geminin gene (Gem; also known as Gmn) in medaka (Oryzias latipes) induces specific forebrain and eye defects that are rescued by Six3. Conversely, loss of Gem (in common with gain of Six3 (ref. 1)) promotes retinal precursor-cell proliferation and results in expanded optic vesicles, markedly potentiating Six3 gain-of-function phenotypes. Our data indicate that the transcription factor Six3 and the replication-initiation inhibitor geminin act antagonistically to control the balance between proliferation and differentiation during early vertebrate eye development.