Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects
Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects
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DOI：
10.1073/pnas.0902408106
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发表时间：
2009-09-01
影响因子：
11.1
通讯作者：
Lees, Jacqueline A.
中科院分区：
文献类型：
--
作者：
Berman, Seth D.;West, Julie C.;Lees, Jacqueline A.
视网膜母细胞瘤肿瘤抑制蛋白pRb是口袋蛋白家族的成员，包括p107和p130。这些蛋白质在调节进入和退出细胞周期中具有明确的作用，并且在促进分化中也具有细胞周期独立的作用。在这里，我们调查口袋蛋白的功能在胚胎发育过程中的重叠，通过使用条件突变等位基因产生Rb; p107双突变胚胎（DKO），在没有胎盘缺陷的情况下发展。这些DKO在e13.5和e14.5之间死亡，比条件Rb或生殖系p107单突变体早得多，后者分别存活至出生或基本上存活。对e13.5 DKO的分析表明，p107突变加剧了中枢神经系统和透镜中pRb缺失导致的表型，但在外周神经系统中不加剧。此外，这些胚胎表现出新的表型，包括血管内皮细胞增殖增加和心脏缺陷，包括右心室双出口（DORV）。DORV至少部分由血管内皮细胞和/或心脏间充质细胞的缺陷引起。这些研究结果表明，新的，重叠的功能pRb和p107在许多小鼠组织。
The retinoblastoma tumor-suppressor protein, pRb, is a member of the pocket protein family that includes p107 and p130. These proteins have well-defined roles in regulating entry into and exit from the cell cycle and also have cell cycle-independent roles in facilitating differentiation. Here we investigate the overlap between pocket protein's function during embryonic development by using conditional mutant alleles to generate Rb; p107 double-mutant embryos (DKOs) that develop in the absence of placental defects. These DKOs die between e13.5 and e14.5, much earlier than either the conditional Rb or the germline p107 single mutants, which survive to birth or are largely viable, respectively. Analyses of the e13.5 DKOs shows that p107 mutation exacerbates the phenotypes resulting from pRb loss in the central nervous system and lens, but not in the peripheral nervous system. In addition, these embryos exhibit novel phenotypes, including increased proliferation of blood vessel endothelial cells, and heart defects, including double-outlet right ventricle (DORV). The DORV is caused, at least in part, by a defect in blood vessel endothelial cells and/or heart mesenchymal cells. These findings demonstrate novel, overlapping functions for pRb and p107 in numerous murine tissues.