Inactivation of Retinoblastoma Protein (Rb1) in the Oocyte: Evidence That Dysregulated Follicle Growth Drives Ovarian Teratoma Formation in Mice.
Inactivation of Retinoblastoma Protein (Rb1) in the Oocyte: Evidence That Dysregulated Follicle Growth Drives Ovarian Teratoma Formation in Mice.
复制标题
DOI：
10.1371/journal.pgen.1005355
复制
发表时间：
2015-07
期刊：
影响因子：
4.5
通讯作者：
Oatley JM
中科院分区：
文献类型：
--
作者：
Yang QE;Nagaoka SI;Gwost I;Hunt PA;Oatley JM
大多数卵巢肿瘤的起源尚不明确。在这里，我们报道了一种新的小鼠模型的发展，在该模型中，肿瘤抑制基因Rb1在卵母细胞中的条件失活导致卵巢畸胎瘤(OTS)的形成。虽然在一些突变的小鼠模型中，孤雌激活的卵母细胞是OT的已知来源，但在Rb1缺陷的卵母细胞中，体外没有观察到增强的孤雌生殖倾向。进一步的分析表明，Rb1条件失活的小鼠卵巢中的卵泡募集和生长受到破坏，导致次级卵泡/腔前卵泡的异常堆积。这些发现支持了生殖细胞和体细胞之间的错误导致卵母细胞过早激活和OTS形成的概念。此外，这些结果表明，即使在没有增强的孤雌生殖激活的情况下，卵泡发生的缺陷和允许的遗传背景也足以驱动OT的发育。因此，我们发现了Rb1在卵母细胞长期生长过程中调节原始卵母细胞进入生长卵泡池以及卵母细胞和颗粒细胞之间的信号传递的新作用。我们的发现，结合其他OT模型的研究数据，表明卵母细胞和卵泡中的体细胞成分之间的协调调节缺陷是OT形成的潜在原因。卵巢畸胎瘤(OTS)是成年女性最常见的生殖细胞肿瘤，但其起源和分子病因尚不清楚。我们发现，在卵母细胞中有条件地缺失肿瘤抑制基因Rb1会导致年轻成年雌性小鼠发生OT。进一步的分析显示，毛囊的招募和生长都受到了干扰。尽管突变的卵母细胞没有表现出更强的孤雌激活倾向--一个被认为是OTS的来源--但在未成熟卵泡的卵母细胞中，减数分裂的过早恢复是明显的。这些发现，结合以前研究的数据，表明卵母细胞-体细胞通讯的缺陷导致协调生长的解偶联，最终损害减数分裂停滞的维持，足以推动OT的发育。
The origin of most ovarian tumors is undefined. Here, we report development of a novel mouse model in which conditional inactivation of the tumor suppressor gene Rb1 in oocytes leads to the formation of ovarian teratomas (OTs). While parthenogenetically activated ooctyes are a known source of OT in some mutant mouse models, enhanced parthenogenetic propensity in vitro was not observed for Rb1-deficient oocytes. Further analyses revealed that follicle recruitment and growth is disrupted in ovaries of mice with conditional inactivation of Rb1, leading to abnormal accumulation of secondary/preantral follicles. These findings underpin the concept that miscues between the germ cell and somatic compartments cause premature oocyte activation and the formation of OTs. Furthermore, these results suggest that defects in folliculogenesis and a permissive genetic background are sufficient to drive OT development, even in the absence of enhanced parthenogenetic activation. Thus, we have discovered a novel role of Rb1 in regulating the entry of primordial oocytes into the pool of growing follicles and signaling between the oocyte and granulosa cells during the protracted process of oocyte growth. Our findings, coupled with data from studies of other OT models, suggest that defects in the coordinated regulation between growth of the oocyte and somatic components in follicles are an underlying cause of OT formation. Ovarian teratomas (OTs) are the most frequent germ cell tumors in adult women, but their origin and molecular etiology remains poorly defined. We found that conditional deletion of the tumor suppressor Rb1 in the oocyte leads to OT development in young adult female mice. Further analysis revealed disturbances in both recruitment and growth of follicles. Although oocytes from mutants did not exhibit an enhanced propensity for parthenogenetic activation–a proposed source of OTs–premature meiotic resumption was evident in oocytes of immature follicles. These findings, together with data from previous studies, suggest that a defect in oocyte-somatic cell communication leading to an uncoupling of coordinated growth and ultimately impaired sustainment of meiotic arrest is sufficient to drive OT development.