Rb is critical in a mammalian tissue stem cell population
Rb is critical in a mammalian tissue stem cell population
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DOI：
10.1101/gad.1485307
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发表时间：
2007-01-01
影响因子：
10.5
通讯作者：
Leone, Gustavo
中科院分区：
文献类型：
--
作者：
Wenzel, Pamela L.;Wu, Lizhao;Leone, Gustavo
小鼠中视网膜母细胞瘤 (Rb) 肿瘤抑制基因的失活会导致异位增殖、细胞凋亡以及胚胎外、神经和红系谱系的分化受损，最终导致胎儿在胚胎 15.5 天时死亡 (E15.5)。在这里，我们发现，滋养层干细胞 (TS) 中 Rb 的特异性缺失（而非滋养层衍生物中的缺失）会导致滋养层过度扩张、胎盘结构破坏以及 E15.5 引起的胎儿死亡。尽管存在严重的胎盘异常，胎儿组织却显得非常正常，这表明胎儿表型的完整表现需要胚胎外组织和胎儿组织中 Rb 的损失。 Rb 的缺失导致 E2f3 表达增加，Rb 和 E2f3 的联合消除显着抑制了 Rb 突变表型。这种拯救似乎是细胞自主的，因为 TS 细胞中 Rb 和 E2f3 的失活恢复了胎盘发育并将胚胎寿命延长至 E17.5。总而言之，这些结果表明，TS 细胞中 Rb 的丢失是导致 Rb-/- 胚胎致死的决定性事件，并揭示了 Rb 在神经和红细胞发育中的胚胎外和胎儿功能的趋同。我们得出结论，Rb 途径在维持哺乳动物干细胞群中发挥着关键作用。
The inactivation of the retinoblastoma ( Rb) tumor suppressor gene in mice results in ectopic proliferation, apoptosis, and impaired differentiation in extraembryonic, neural, and erythroid lineages, culminating in fetal death by embryonic day 15.5 ( E15.5). Here we show that the specific loss of Rb in trophoblast stem ( TS) cells, but not in trophoblast derivatives, leads to an overexpansion of trophoblasts, a disruption of placental architecture, and fetal death by E15.5. Despite profound placental abnormalities, fetal tissues appeared remarkably normal, suggesting that the full manifestation of fetal phenotypes requires the loss of Rb in both extraembryonic and fetal tissues. Loss of Rb resulted in an increase of E2f3 expression, and the combined ablation of Rb and E2f3 significantly suppressed Rb mutant phenotypes. This rescue appears to be cell autonomous since the inactivation of Rb and E2f3 in TS cells restored placental development and extended the life of embryos to E17.5. Taken together, these results demonstrate that loss of Rb in TS cells is the defining event causing lethality of Rb-/- embryos and reveal the convergence of extraembryonic and fetal functions of Rb in neural and erythroid development. We conclude that the Rb pathway plays a critical role in the maintenance of a mammalian stem cell population.