Figure 5.

Hypothetical working model for SMAD2/3 signaling in mediating gonadal tumorigenesis in inhibin-deficient female mice. (A) In the WT ovary, the signaling of activins is finely tuned by inhibins, which is important in the maintenance of normal granulosa cell function, follicular development, and fertility. (B) In the absence of inhibins, activin signaling is potentiated with increased production of activins by the gonads and tumors due to the loss of antagonism by inhibins. Superphysiological levels of activins can signal through both SMAD2 and SMAD3 in the ovary. As demonstrated by the Inha/Smad3 double knockout mouse model [28], ovarian tumor development is attenuated in Inha null mice lacking SMAD3, implying that the function of SMAD3 is not fully compensated by SMAD2. Complementarily, the Inha/Smad2 cKO mouse model generated in the current study suggests that SMAD3 can potentially mediate essential tumorigenic signals of activins in the Inha null mice (C). However, our model does not rule out the potential involvement of SMAD-independent signaling (dotted lines) in inhibin-deficient ovarian tumor development or the possibility that SMAD2 may not be involved in gonadal tumor development.