Wenzel Pamela L, Wu Lizhao, de Bruin Alain, Chong Jean-Leon, Chen Wen-Yi, Dureska Geoffrey, Sites Emily, Pan Tony, Sharma Ashish, Huang Kun, Ridgway Randall, Mosaliganti Kishore, Sharp Richard, Machiraju Raghu, Saltz Joel, Yamamoto Hideyuki, Cross James C, Robinson Michael L, Leone Gustavo
Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Genes Dev. 2007 Jan 1;21(1):85-97. doi: 10.1101/gad.1485307.
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.
小鼠视网膜母细胞瘤（Rb）肿瘤抑制基因的失活会导致胚外、神经和红系谱系中出现异位增殖、细胞凋亡及分化受损，最终在胚胎第15.5天（E15.5）导致胎儿死亡。在此我们表明，滋养层干细胞（TS）而非滋养层衍生物中Rb的特异性缺失会导致滋养层过度扩张、胎盘结构破坏，并在E15.5时导致胎儿死亡。尽管胎盘存在严重异常，但胎儿组织看起来明显正常，这表明胎儿表型的完全显现需要胚外组织和胎儿组织中Rb均缺失。Rb的缺失导致E2f3表达增加，Rb和E2f3的联合缺失显著抑制了Rb突变体表型。这种拯救似乎是细胞自主性的，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。综上所述，这些结果表明TS细胞中Rb的缺失是导致Rb（-/-）胚胎致死的决定性事件，并揭示了Rb在神经和红系发育中胚外和胎儿功能的趋同。我们得出结论，Rb通路在维持哺乳动物干细胞群体中起关键作用。
