Tumor Necrosis Factor (TNF) Receptor Type 2 Is an Important Mediator of TNF alpha Function in the Mouse Ovary1

Abstract

It is believed that a finite pool of primordial follicles is established during embryonic and neonatal life. At birth, the mouse ovary consists of clusters of interconnected oocytes surrounded by pregranulosa cells. Shortly after birth these structures, termed germ cell cysts or nests (GCN), break down to facilitate primordial follicle formation. Tumor necrosis factor alpha (TNF) is a widely expressed protein with myriad functions. TNF is expressed in the ovary and may regulate GCN breakdown in rats. We investigated whether it participates in GCN breakdown and follicle formation in mice by using an in vitro ovary culture system as well as mutant animal models. We found that TNF and both receptors (TNFRSF1A and TNFRSF1B) are expressed in neonatal mouse ovaries and that TNF promotes oocyte death in neonatal ovaries in vitro. However, deletion of either receptor did not affect follicle endowment, suggesting that TNF does not regulate GCN breakdown in vivo. Tnfrsf1b deletion led to an apparent acceleration of follicular growth and a concomitant expansion of the primordial follicle population. This expansion of the primordial follicle population does not appear to be due to decreased primordial follicle atresia, although this cannot be ruled out completely. This study demonstrates that mouse oocytes express both TNF receptors and are sensitive to TNF-induced death. Additionally, TNFRSF1B is demonstrated to be an important mediator of TNF function in the mouse ovary and an important regulator of folliculogenesis.

The dynamics of the primordial follicle reserve

“…Because primordial follicle formation is associated with significant germ cell attrition (Kezele et al 2002, Pepling 2006, investigations into the associated death mechanisms have been topical and numerous laboratories, using both in vivo and in vitro techniques, have concluded that apoptosis (Coucouvanis et al 1993, De Pol et al 1997, Pepling & Spradling 2001, De Felici et al 2008, Xu et al 2011, autophagy (Lobascio et al 2007, De Felici et al 2008, Rodrigues et al 2009, and direct extrusion from the ovaries (Rodrigues et al 2009) are contributory mechanisms of pre-and neonatal oocyte demise. Apoptosis, the most favored of the three, has been demonstrated not only in mouse models directly targeting Bcl2 and caspase genes (Bergeron et al 1998, Perez et al 1999, Rucker et al 2000, Flaws et al 2001, 2006, Alton & Taketo 2007, Ghafari et al 2007, Greenfeld et al 2007, Gursoy et al 2008 but also because of the findings from several gene knockout (or overexpressor) models belonging to the tumor necrosis factor pathway (Marcinkiewicz et al 2002, Greenfeld et al 2007), PAR family (Wen et al 2009), and TGFb family (Kimura et al 2011), all of which actively participate in oocyte loss by regulating apoptosis.…”

Macrophage secretions modulate the steroidogenesis of polycystic ovary in rats: Effect of testosterone on macrophage pro-inflammatory cytokines

“…TNFα stimulates proliferation and steroidogenesis in in vitro rat theca cells facilitating the effects of insulin and IGF-I (Spaczynski et al, 1999). Also, TNFα induces apoptosis and anovulation in the ovaries (Greenfeld et al, 2007).…”

Effects of Diethylstilbestrol on Programmed Oocyte Death and Induction of Polyovular Follicles in Neonatal Mouse Ovaries1

“…Tumor necrosis factor (TNF), a factor inducing apoptosis, plays various roles in the ovary, including promotion of granulosa cell proliferation [17] and induction of cell death of oocytes, granulosa cells, and luteal cells [18]. Tumor necrosis factor promotes germ cell cyst breakdown and follicle formation in neonatal rat ovary in vitro [19], and the addition of TNF reduces the primordial follicle number in the neonatal mouse ovary in vitro [20]. Ovaries from TNF receptor 1 (Tnfr1) or Tnfr2 KO mice, however, do not exhibit a decrease in primordial follicles compared with wild-type (WT) mice [20].…”