The Wilms tumor protein Wt1 contributes to female fertility by regulating oviductal proteostasis
| Autor: | Jörg Herrmann, Andreas J. R. Habenicht, Christoph Englert, Zhao-Qi Wang, Dagmar Kruspe, Hendrik Nolte, Matthias Platzer, Marcus Krüger, Bettina Toth, Abinaya Nathan, Verena Holschbach, Marco Groth, Peter Reinhardt, Tjard Jörß |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Proteases congenital hereditary and neonatal diseases and abnormalities media_common.quotation_subject Mutation Missense Fertility Oviducts Biology medicine.disease_cause urologic and male genital diseases Wilms Tumor 03 medical and health sciences Mice Internal medicine Genetics medicine Missense mutation Animals Humans WT1 Proteins Molecular Biology Genetics (clinical) media_common Zinc finger Zinc finger transcription factor Mice Knockout Mutation Binding Sites Base Sequence urogenital system fungi Zinc Fingers General Medicine Exons Articles Wilms Tumor Protein female genital diseases and pregnancy complications Cell biology DNA-Binding Proteins Disease Models Animal 030104 developmental biology Proteostasis Endocrinology Female Infertility Female Transcription Factors |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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