WNT4 is required for normal ovarian follicle development and female fertility.
To study the role of WNT4 in the postnatal ovary, a mouse strain bearing a floxed Wnt4 allele was created and mated to the Amhr2(tm3(cre)Bhr) strain to target deletion of Wnt4 to granulosa cells. Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) mice had reduced ovary weights and produced smaller litters (P<0.05). Serial follicle counting demonstrated that Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) mice were born with a normal ovarian reserve and maintained normal numbers of small follicles until puberty but had only 25.2% of the normal number of healthy antral follicles. Some Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) mice had no antral follicles or corpora lutea and underwent premature follicle depletion. RT-PCR analyses of Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) granulosa cells and cultured granulosa cells that overexpress WNT4 demonstrated that WNT4 regulates the expression of Star, Cyp11a1, and Cyp19, steroidogenic genes previously identified as downstream targets of the WNT signaling effector CTNNB1. Decreased serum progesterone levels were found in immature, gonadotropin-treated Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) mice (P<0.05). WNT4- and CTNNB1-overexpressing cultured granulosa cells were analyzed by microarray for alterations in gene expression, which showed that WNT4 regulates additional genes involved in late follicle development via the WNT/CTNNB1 signaling pathway. Together, these data indicate that WNT4 is required for normal antral follicle development and may act by regulating granulosa cell functions including steroidogenesis.
Boyer
Alexandre
A
Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, C.P. 5000, St.-Hyacinthe, QC, Canada J2S 7C6.
Lapointe
Evelyne
E
Zheng
Xiaofeng
X
Cowan
Robert G
RG
Li
Huaiguang
H
Quirk
Susan M
SM
DeMayo
Francesco J
FJ
Richards
JoAnne S
JS
Boerboom
Derek
D
D000818:Animals; D005260:Female; D005298:Fertility; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D006080:Ovarian Follicle; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000235:genetics; D013256:Steroids / Q000096:biosynthesis; D051153:Wnt Proteins / Q000502:physiology*; D060528:Wnt4 Protein; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D013256:Steroids; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051176:beta Catenin; D013250:Steroid Hydroxylases