Inactivation of Retinoblastoma Protein (Rb1) in the Oocyte: Evidence That Dysregulated Follicle Growth Drives Ovarian Teratoma Formation in Mice.

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.

Retinoblastoma protein (RB1) controls fate determination in stem cells and progenitors of the mouse male germline.

Continual spermatogenesis is the cornerstone of male fertility and relies on the actions of an undifferentiated spermatogonial population comprised of stem cells and progenitors. A foundational spermatogonial stem cell (SSC) pool is established during postnatal development that serves as a self-renewing reservoir from which progenitor spermatogonia arise that transiently amplify in number before committing to terminal differentiation. At present, the underlying molecular mechanisms governing these actions are undefined. Using conditional mutant mouse models, we investigated whether function of the undifferentiated spermatogonial population during postnatal life is influenced by the tumor suppressor protein RB1. Spermatogenesis initiates in mice with conditional inactivation of Rb1 in prospermatogonial precursors, but the germline is progressively lost upon aging due to impaired renewal of the undifferentiated spermatogonial population. In contrast, continual spermatogenesis is sustained following Rb1 inactivation in progenitor spermatogonia, but some cells transform into a carcinoma in situ-like state. Furthermore, knockdown of Rb1 abundance within primary cultures of wild-type undifferentiated spermatogonia impairs maintenance of the SSC pool, and some cells are invasive of the basement membrane after transplant into recipient testes, indicating acquisition of tumorigenic properties. Collectively, these findings indicate that RB1 plays an essential role in establishment of a self-renewing SSC pool and commitment to the spermatogenic lineage within progenitor spermatogonia.