Wnt4, a pleiotropic signal for controlling cell polarity, basement membrane integrity, and antimullerian hormone expression during oocyte maturation in the female follicle

Abstract

Wnt4 is a key signal that channels the developmental fate of the indifferent mammalian gonad toward the ovary, but whether Wnt4 has later roles during ovary development remains unknown. To investigate this, we inactivated the Wnt4 gene by crossing Amhr2Cre and doxycycline-inducible Rosa(rtTA)-knock-in Cre mice with mice carrying a floxed Wnt4 allele and used a novel Wnt4(mCherry)-knock-in mouse. In these models, ovarian folliculogenesis was compromised, and female fertility was severely reduced, and Wnt4 deficiency eventually led to premature ovarian failure. These anomalies were associated with cell polarity defects in the follicle. Within the follicle, laminin and type IV collagen assembled ectopic basement membrane-like structures, the cell adherens junction components N-cadherin and β-catenin lost their polarized expression pattern, and expression of the gap junction protein connexin 43 was reduced by ~30% when compared with that of the controls. Besides these changes, expression of antimüllerian hormone (Amh) was inhibited in the absence of Wnt4 signaling in vivo. Consistent with this, Wnt4 signaling up-regulated Amh gene expression in KK1 cells in vitro. Thus, Wnt4 signaling is necessary during maturation of the ovarian follicles, where it coordinates expression of Amh, cell survival, and polarized organization of the follicular cells.

FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development

“…Reduced levels of Amh may also be related to the activity of FOXL2 (18). These altered gene expression profiles are consistent with abnormal follicle development and the dramatic loss of oocytes that is also observed in ovaries of the Emx2, Rspo1, and Wnt4 knockout mice (24,107,108). In addition, in the embryonic ovary activin can cause apoptosis of germ cells (116).…”

“…The tumor cells also retain expression of factors that regulate FOXL2 activity, such as Lats1/2 (100 -102; data not shown). However, they lack expression of other key genes that control granulosa cell fate specification and follicle formation (Emx2, Fst, Lgr5, Nr0b1, and Rspo1) and differentiation (Amh, Fshr, and Lhcgr) (23,24,83,(103)(104)(105)(106)(107)(108)(109). The loss of Rspo1 likely contributes to the decreased expression of Emx2 and Amh because both are regulated by WNT4 signaling in granulosa cells (24).…”

Cloning and characterization of wnt4a gene and evidence for positive selection in half-smooth tongue sole (Cynoglossus semilaevis)

“…New functions for wnt4 genes have been found in mammals, fishes, and other vertebrates333435. Wnt4 genes have been described in some teleosts, though few species have been comprehensively and systematically studied.…”

Single cell transcriptome profiling revealed differences in gene expression during oocyte maturation in Haimen white goats

“…Maturation of mammalian oocytes is a complex physiological process involving a large number of regulatory factors, cell structures, and different signaling pathways (Ball et al, 2014;Dang-Nguyen et al, 2014;Prunskaite-Hyyryläinen et al, 2014). For example, the cyclic adenosine monophosphate (cAMP) signaling pathway is necessary for maintaining meiosis, whereas the MAPK signaling pathway plays an important role in meiosis initiation, spindle assembly, and M2 arrest.…”