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Hum Mol Genet. 2017 May 1;26(9):1694-1705. doi: 10.1093/hmg/ddx075.

The Wilms tumor protein Wt1 contributes to female fertility by regulating oviductal proteostasis.

Author information

1
Molecular Genetics Lab.
2
Genomic Stability Lab.
3
Genome Analysis Lab, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
4
Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
5
Institute for Vascular Medicine, Jena University Hospital, Jena, Germany.
6
Department of Gynecology and Obstetrics, Hufeland Klinikum, 99425 Weimar, Germany.
7
Department of Gynecological Endocrinology and Fertility Disorders, University Hospital Heidelberg, 69120 Heidelberg, Germany.
8
Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, 07745 Jena, Germany.

Abstract

Although the zinc finger transcription factor Wt1 has been linked to female fertility, its precise role in this process has not yet been understood. We have sequenced the WT1 exons in a panel of patients with idiopathic infertility and have identified a missense mutation in WT1 in one patient out of eight. This mutation leads to an amino acid change within the zinc finger domain and results in reduced DNA binding. We utilized Wt1+/- mice as a model to mechanistically pinpoint the consequences of reduced Wt1 levels for female fertility. Our results indicate that subfertility in Wt1+/- female mice is a maternal effect caused by the Wt1-dependent de-regulation of Prss29, encoding a serine protease. Notably, blocking Prss29 activity was sufficient to rescue subfertility in Wt1+/- mice indicating Prss29 as a critical factor in female fertility. Molecularly, Wt1 represses expression of Prss29. De-repression and precocious expression of Prss29 in the oviduct of Wt1+/- mice interferes with pre-implantation development. Our study reveals a novel role for Wt1 in early mammalian development and identifies proteases as critical mediators of the maternal-embryonic interaction. Our data also suggest that the role of Wt1 in regulating fertility is conserved in mammals.

PMID:
28334862
PMCID:
PMC5411738
DOI:
10.1093/hmg/ddx075
[Indexed for MEDLINE]
Free PMC Article

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