title: Wt1 functions in ovarian follicle development by regulating granulosa cell differentiation.
abstract: The Wt1 gene encodes a nuclear transcription factor that is specifically expressed in ovarian granulosa cells. However, the physiological significance of Wt1 in ovarian follicle development remains elusive. In this study, we found that Wt1(+/R394W) mice were grossly normal, however, the females displayed severe reproductive defects. Only ∼15% of the Wt1(+/R394W) females became pregnant after mating with wild-type males, compared with 88.2% of control females. Further study revealed that the subfertility of Wt1(+/R394W) females was caused by aberrant ovarian follicle development. Compared with control females, the ovary size and the number of developing follicles was significantly decreased in Wt1 mutant ovaries which was very similar to premature ovarian failure (POF) in human patients. The results of in vitro studies demonstrated that the expression of follicle stimulating hormone receptor (FSHR), 3β-hydroxysteroid dehydrogenase and Aromatase was inhibited by Wt1 in granulosa cells, and mutation of Wt1 resulted in the upregulation of these genes and in the premature differentiation of granulosa cells. We also found that Wt1 was likely involved in granulosa cell development via the regulation of E-cadherin and Par6b expression. Mutation in Wt1 caused defects in polarity establishment in granulosa cells, which also likely contributed to the observed aberrant follicle development. The results of this study provide new mechanisms for understanding the regulation of ovarian follicle development and potential pathological cause of POF in human patients.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaona
authors.initials: X
authors.lastname: Wang
authors.forename: Junling
authors.initials: J
authors.lastname: Yang
authors.forename: Dahua
authors.initials: D
authors.lastname: Chen
authors.forename: Vicki
authors.initials: V
authors.lastname: Huff
authors.forename: Yi-Xun
authors.initials: YX
authors.lastname: Liu
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D016764:Cell Polarity; D005260:Female; D005298:Fertility; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D006080:Ovarian Follicle / Q000473:pathology / Q000502:physiology*; D010060:Ovulation; D011247:Pregnancy; D016649:Primary Ovarian Insufficiency / Q000473:pathology; D011962:Receptors, FSH / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D011962:Receptors, FSH; D025721:WT1 Proteins; D015096:3-Hydroxysteroid Dehydrogenases; D001141:Aromatase