Maandag E C, van der Valk M, Vlaar M, Feltkamp C, O'Brien J, van Roon M, van der Lugt N, Berns A, te Riele H
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam.
EMBO J. 1994 Sep 15;13(18):4260-8. doi: 10.1002/j.1460-2075.1994.tb06746.x.
The requirement for a functional retinoblastoma gene, Rb-1, in murine development around days 12-15 of gestation precludes monitoring the effect of loss of Rb-1 function on later stages of development and on tumorigenesis in adult mice. Here we describe the developmental rescue of embryonic stem cells carrying two inactive Rb-1 alleles in chimeric mice. Rb-1- cells contributed substantially to most tissues in adult chimeras, including blood, liver and central nervous system, which were severely affected in pure Rb-1- embryos. The adult chimeric erythroid compartment appeared completely normal, but an increased number of nucleated red cells was observed during fetal liver erythropoiesis in highly chimeric embryos. No ostensive abnormalities were seen in the developing and adult CNS. However, the developing retina of chimeric Rb-1- embryos showed ectopic mitoses and substantial cell degeneration, while the contribution of Rb-1- cells to the adult retina was much reduced. Moreover, the formation of lens fibre cells was severely disturbed. No retinoblastomas developed in any of these mice. Instead, nearly all animals died of pituitary gland tumours which were exclusively derived from Rb-1- cells.
在妊娠第12 - 15天左右的小鼠发育过程中，功能性视网膜母细胞瘤基因Rb - 1是必需的，这使得无法监测Rb - 1功能丧失对发育后期以及成年小鼠肿瘤发生的影响。在此，我们描述了在嵌合小鼠中携带两个无活性Rb - 1等位基因的胚胎干细胞的发育拯救情况。Rb - 1-细胞对成年嵌合体的大多数组织，包括血液、肝脏和中枢神经系统，都有显著贡献，而在纯合Rb - 1-胚胎中这些组织会受到严重影响。成年嵌合红细胞区看起来完全正常，但在高度嵌合胚胎的胎儿肝脏红细胞生成过程中，观察到有核红细胞数量增加。在发育中的和成年的中枢神经系统中未发现明显异常。然而，嵌合Rb - 1-胚胎发育中的视网膜显示出异位有丝分裂和大量细胞退化，而Rb - 1-细胞对成年视网膜的贡献则大大减少。此外，晶状体纤维细胞的形成受到严重干扰。这些小鼠中没有一只发生视网膜母细胞瘤。相反，几乎所有动物都死于垂体肿瘤，这些肿瘤完全源自Rb - 1-细胞。
