Robanus-Maandag E, Dekker M, van der Valk M, Carrozza M L, Jeanny J C, Dannenberg J H, Berns A, te Riele H
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Genes Dev. 1998 Jun 1;12(11):1599-609. doi: 10.1101/gad.12.11.1599.
Hemizygosity for the retinoblastoma gene RB in man strongly predisposes to retinoblastoma. In the mouse, however, Rb hemizygosity leaves the retina normal, whereas in Rb-/- chimeras pRb-deficient retinoblasts undergo apoptosis. To test whether concomitant inactivation of the Rb-related gene p107 is required to unleash the oncogenic potential of pRb deficiency in the mouse retina, we inactivated both Rb and p107 by homologous recombination in embryonic stem cells and generated chimeric mice. Retinoblastomas were found in five out of seven adult pRb/p107-deficient chimeras. The retinal tumors showed amacrine cell differentiation, and therefore originated from cells committed to the inner but not the outer nuclear layer. Retinal lesions were already observed at embryonic day 17.5. At this stage, the primitive nuclear layer exhibited severe dysplasia, including rosette-like arrangements, and apoptosis. These findings provide formal proof for the role of loss of Rb in retinoblastoma development in the mouse and the first in vivo evidence that p107 can exert a tumor suppressor function.
人类中视网膜母细胞瘤基因RB的半合子状态极易引发视网膜母细胞瘤。然而，在小鼠中，Rb半合子状态下视网膜正常，而在Rb-/-嵌合体中，缺乏pRb的视网膜母细胞会发生凋亡。为了测试是否需要同时使Rb相关基因p107失活才能释放pRb缺乏在小鼠视网膜中的致癌潜能，我们通过胚胎干细胞中的同源重组使Rb和p107均失活，并生成了嵌合小鼠。在7只成年pRb/p107缺陷型嵌合体小鼠中，有5只发现了视网膜母细胞瘤。视网膜肿瘤表现出无长突细胞分化，因此起源于向内核层而非外核层分化的细胞。在胚胎第17.5天就已观察到视网膜病变。在此阶段，原始核层表现出严重发育异常，包括玫瑰花结样排列和凋亡。这些发现为Rb缺失在小鼠视网膜母细胞瘤发生中的作用提供了正式证据，并首次在体内证明p107可发挥肿瘤抑制功能。
