title: Wnt4, a pleiotropic signal for controlling cell polarity, basement membrane integrity, and antimüllerian 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.
authors.affiliation: 1Laboratory of Developmental Biology, Department of Medical Biochemistry and Molecular Biology, University of Oulu and Biocenter Oulu, Aapistie 5, P. O. Box 5000, FIN-90220, Oulu, Finland. seppo.vainio@oulu.fi.
authors.forename: Renata
authors.initials: R
authors.lastname: Prunskaite-Hyyryläinen
authors.forename: Jingdong
authors.initials: J
authors.lastname: Shan
authors.forename: Antti
authors.initials: A
authors.lastname: Railo
authors.forename: Krista M
authors.initials: KM
authors.lastname: Heinonen
authors.forename: Ilkka
authors.initials: I
authors.lastname: Miinalainen
authors.forename: Wenying
authors.initials: W
authors.lastname: Yan
authors.forename: Bairong
authors.initials: B
authors.lastname: Shen
authors.forename: Claude
authors.initials: C
authors.lastname: Perreault
authors.forename: Seppo J
authors.initials: SJ
authors.lastname: Vainio
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D054304:Anti-Mullerian Hormone / Q000235:genetics* / Q000378:metabolism; D001485:Basement Membrane / Q000378:metabolism*; D016764:Cell Polarity / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006107:Granulosa Cells / Q000378:metabolism / Q000648:ultrastructure; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009865:Oocytes / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D006080:Ovarian Follicle / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000235:genetics; D060528:Wnt4 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D060528:Wnt4 Protein; D054304:Anti-Mullerian Hormone
keywords: cell polarity; ovarian development; premature ovarian failure; sex determination