The Wilms tumor protein Wt1 contributes to female fertility by regulating oviductal proteostasis.
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.
Molecular Genetics Lab.
Abinaya
A
Nathan
Molecular Genetics Lab.
Peter
P
Reinhardt
Molecular Genetics Lab.
Dagmar
D
Kruspe
Genomic Stability Lab.
Tjard
T
Jörß
Genome Analysis Lab, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
Marco
M
Groth
Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Hendrik
H
Nolte
Institute for Vascular Medicine, Jena University Hospital, Jena, Germany.
Andreas
A
Habenicht
Department of Gynecology and Obstetrics, Hufeland Klinikum, 99425 Weimar, Germany.
Jörg
J
Herrmann
Department of Gynecological Endocrinology and Fertility Disorders, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Verena
V
Holschbach
Department of Gynecological Endocrinology and Fertility Disorders, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Bettina
B
Toth
Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Marcus
M
Krüger
Genomic Stability Lab.
Zhao-Qi
ZQ
Wang
Genome Analysis Lab, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
Matthias
M
Platzer
Molecular Genetics Lab.|Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, 07745 Jena, Germany.
Christoph
C
Englert
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005091:Exons; D005260:Female; D005298:Fertility / Q000502:physiology; D006801:Humans; D007247:Infertility, Female / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D010057:Oviducts / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism*; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism*; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D014157:Transcription Factors; D025721:WT1 Proteins; C583751:WT1 protein, human