لخّصلي

Studies show that precise regulation of canonical WNT signaling is crucial for ovarian follicle development and fertility. Disruptions, such as through Rspo1 amplification or Wnt5a deletion, lead to ovarian subfertility. Similarly, aberrant WNT signaling is implicated in granulosa cell tumors (GCTs), with increased β-catenin levels observed in these tumors and epigenetic silencing of the WNT antagonist DKK3. Genetic models activating WNT signaling demonstrate a significant increase in GCT development. This study investigates the role of APC2, a known regulator of β-catenin/WNT signaling, in ovarian folliculogenesis, fertility, and GCT formation. While APC2's role in regulating WNT signaling is established in other tissues, its function in the adult ovary remains largely unexplored.

17.6% of female mice were infertile and characterized by early follicle depletion, but with no concomitant change in total activated β-catenin levels [14]. Overactivation of canonical WNT signalling also has deleterious effects on ovarian homeostasis. Ovarian amplification of Rspo1 [15], deletion of Wnt5a (antagonist of canonical WNT signalling) [16] or expression of dominant stable β-catenin [10, 17] all resulted in up-regulated ovarian WNT signalling and ovarian subfertility caused by disruption of follicle growth [16, 17], ovulation and luteinisation [10, 15]. Taken together, these findings indicate the importance of tight regulation of canonical WNT signalling in growing follicles.
Human ovarian tumours are classified into epithelial ovarian cancers (90%), sex cord-stromal tumours (7%) and germ cell tumours (3%). Granulosa cell tumours (GCTs), which originate from granulosa cells of ovarian follicles, account for more than half of sex cord-stromal tumours [18]. WNT signalling mis-regulation has been implicated in adult GCT formation, as several studies have demonstrated increased β-catenin protein levels therein, with nuclear localisation in some cases [17, 19, 20]. A recent molecular study of GCTs showed epigenetic silencing of DKK3, the gene coding for the WNTsignalling antagonist Dickkopf, implying a need for WNT signalling activation in GCT development (25, 26) . Furthermore, GEMMs in which WNT signalling was activated via the introduction of a gain-of-function mutation of R-spondin1 [15], or a degradation-resistant βcatenin [17], resulted in 15.8% or 57% of mice developing adult GCTs respectively.
Here, for the first time, we address the importance of APC2 in ovarian folliculogenesis, fertility and GCT formation. The ability of APC2 to regulate the β-catenin/ WNT signalling pathway has been demonstrated in
Drosophila and in cancer cell lines [21–25]. Structurally, APC2 possesses AXIN1 and β-catenin binding sites, which enable it to destabilize β-catenin, targeting it for degradation and suppressing its transcriptional activity [22, 26], in addition to the APC-basic domain which enables it to regulate cytoskeleton and microtubule association [27–31] and spindle anchoring during mitosis [32]. Importantly, however, in an in vivo setting, APC2dependent regulation of WNT signalling is tissuespecific, occurring in the liver and intestine but not in the mammary gland [33, 34]. Little is known about how APC2 functions in adult ovaries, but