WNT4/β-Catenin Pathway Maintains Female Germ Cell Survival by Inhibiting Activin βB in the Mouse Fetal Ovary

Abstract

Female germ cells are essential for organogenesis of the ovary; without them, ovarian follicles do not form and functional and structural characteristics of the ovary are lost. We and others showed previously that when either Wnt4 or β-catenin was inactivated in the fetal ovary, female germ cells underwent degeneration. In this study, we set out to understand whether these two factors belong to the same pathway and how they maintain female germ cell survival. We found that activation of β-catenin in somatic cells in the Wnt4 knockout ovary restored germ cell numbers, placing β-catenin downstream of WNT4. In the absence of Wnt4 or β-catenin, female germ cells entered meiosis properly; however, they underwent apoptosis afterwards. Activin βB (Inhbb), a subunit of activins, was upregulated in the Wnt4 and β-catenin knockout ovaries, suggesting that Inhbb could be the cause for the loss of female germ cells, which are positive for activin receptors. Indeed, removal of Inhbb in the Wnt4 knockout ovaries prevented female germ cells from undergoing degeneration. We conclude that WNT4 maintains female germ cell survival by inhibiting Inhbb expression via β-catenin in the somatic cells. Maintenance of female germ cells hinge upon a delicate balance between positive (WNT4 and β-catenin) and negative (activin βB) regulators derived from the somatic cells in the fetal ovary.

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

“…TOPGAL mice carry three multimerized LEF/TCF consensus binding sites in front of the LacZ reporter, which may suggest that CTNNB1 in the developing gonad may act in a LEF/TCF-independent way (A A Chassot, unpublished data). Rspo1 and Wnt4 control WNT/b-catenin activation in the XX gonads as evidenced by rescue experiments (Chassot et al 2008a, Maatouk et al 2008, Liu et al 2010. However, in the absence of Wnt4 or Rspo1, Ctnnb1 transcriptional activity is only partially decreased as Axin2 remains expressed in the coelomic region of the XX gonads (Chassot et al 2012), suggesting that there remain other positive regulators of WNT/ b-catenin signaling to be identified.…”

“…The cellular context is essential for the choice of the pathway to be activated as exemplified by WNT4. While WNT4 is able to activate canonical WNT signaling in gonadal development (Maatouk et al 2008, Liu et al 2010), it appears to induce CTNNB1-independent pathways in the kidney (Burn et al 2011). In addition to its role in canonical WNT signaling, CTNNB1 is also an important component of adherent junctions, which regulates patterning and morphogenesis.…”

“…In the Wnt4 mutant gonads, the expression of Stra8 is also weak while the expression of Pou5f1 is maintained at 14.5 dpc, indicating a delay in meiosis entry . However, the number of meiotic germ cells in the Wnt4 K/K ovaries is normal when compared with a WT ovary at 15.5 dpc (Yao et al 2004) and surviving germ cells usually express meiotic markers (Maatouk et al 2013), before undergoing apoptosis through increasing Activin bb expression (Liu et al 2010). The precise mechanisms of how Rspo1 and Wnt4 affect meiosis entry remain yet to be elucidated.…”

Transcriptomic analysis reveals key regulators of mammogenesis and the pregnancy-lactation cycle

“…It promotes apoptosis through binding insulin-like factor. It was reported that Inhbb regulates apoptosis based on its interactions with Wnt4 [54] and it may be involved in apoptosis of the mammary gland. However, the present study shows that Wnt4 expression levels were not as pronounced as we expected and Wnt4 may have different target genes for regulating mammary epithelial apoptosis.…”

Role and Function of Wnts in the Regulation of Myogenesis: When Wnt Meets Myostatin

“…In mammals, highly transforming Wnts have been associated to the canonical Wnt/ -catenin pathway, whereas non-transforming Wnts have been associated activate to the non-canonical pathway [4,6]. It is noteworthy that this binary classification is becoming obsolete, thus although Wnt4 was originally described as a non-canonical Wnt (nontransforming Wnt), it has also been implicated in the activation or inhibition of the canonical Wnt pathway [55,56,57,58,59,60,61]. Wnt7a has also been implicated in both canonical and non-canonical Wnt signaling depending on the cell and tissue context [62,63].…”