Oocyte-specific Wee1-like protein kinase 2 is dispensable for fertility in mice

Wee1-like protein kinase 2 (WEE2) is an oocyte-specific protein tyrosine kinase involved in the regulation of oocyte meiotic arrest in humans. As such, it has been proposed as a candidate for non-hormonal female contraception although pre-clinical models have not been reported. Therefore, we develop...

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Veröffentlicht in:PloS one 2023-08, Vol.18 (8), p.e0289083
Hauptverfasser: Nozawa, Kaori, Liao, Zian, Satouh, Yuhkoh, Geng, Ting, Ikawa, Masahito, Monsivais, Diana, Matzuk, Martin M
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Liao, Zian
Satouh, Yuhkoh
Geng, Ting
Ikawa, Masahito
Monsivais, Diana
Matzuk, Martin M
description Wee1-like protein kinase 2 (WEE2) is an oocyte-specific protein tyrosine kinase involved in the regulation of oocyte meiotic arrest in humans. As such, it has been proposed as a candidate for non-hormonal female contraception although pre-clinical models have not been reported. Therefore, we developed two novel knockout mouse models using CRISPR/Cas9 to test loss-of-function of Wee2 on female fertility. A frameshift mutation at the Wee2 translation start codon in exon 2 had no effect on litter size, litter production, or the ability of oocytes to maintain prophase I arrest. Because of the lack of a reproductive phenotype, we additionally generated a Wee2 allele with a large deletion by removing all coding exons. While there was no difference in the total number of litters produced, homozygous Wee2 female knockout mice with the larger deletion produced fewer pups than heterozygous littermates. Furthermore, there was no difference for key reproductive parameters measured in the mouse models, including ovarian weight, number of ovulated oocytes, or oocytes that underwent in vitro maturation. Therefore, as loss of Wee2 in mice shows only minor effects on overall fecundity, contraceptive development with WEE2 should consider exploiting alternative properties such as gain-of-function or protein-protein interactions, as Wee2 loss-of-function is likely complicated by biological redundancies with other proteins co-expressed in oocytes.
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As such, it has been proposed as a candidate for non-hormonal female contraception although pre-clinical models have not been reported. Therefore, we developed two novel knockout mouse models using CRISPR/Cas9 to test loss-of-function of Wee2 on female fertility. A frameshift mutation at the Wee2 translation start codon in exon 2 had no effect on litter size, litter production, or the ability of oocytes to maintain prophase I arrest. Because of the lack of a reproductive phenotype, we additionally generated a Wee2 allele with a large deletion by removing all coding exons. While there was no difference in the total number of litters produced, homozygous Wee2 female knockout mice with the larger deletion produced fewer pups than heterozygous littermates. Furthermore, there was no difference for key reproductive parameters measured in the mouse models, including ovarian weight, number of ovulated oocytes, or oocytes that underwent in vitro maturation. Therefore, as loss of Wee2 in mice shows only minor effects on overall fecundity, contraceptive development with WEE2 should consider exploiting alternative properties such as gain-of-function or protein-protein interactions, as Wee2 loss-of-function is likely complicated by biological redundancies with other proteins co-expressed in oocytes.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0289083</identifier><identifier>PMID: 37527245</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Animal models ; Animals ; Biology and Life Sciences ; Cell cycle ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Contraception ; Contraceptives ; CRISPR ; Cyclin-dependent kinases ; Deletion ; Embryos ; Engineering and Technology ; Exons ; Fecundity ; Female ; Females ; Fertility ; Fertility - genetics ; Frameshift mutation ; Gametocytes ; Health aspects ; Histology ; Humans ; In vitro fertilization ; Infertility ; Kinases ; Litter size ; Medicine ; Medicine and Health Sciences ; Meiosis ; Mice ; Mutation ; Oocytes ; Oocytes - metabolism ; Ovaries ; Ovulation ; Phenotypes ; Phosphorylation ; Prophase ; Protein interaction ; Protein Kinases - metabolism ; Protein-protein interactions ; Protein-tyrosine kinase ; Protein-Tyrosine Kinases - genetics ; Protein-Tyrosine Kinases - metabolism ; Proteins ; Research and Analysis Methods ; Statistical significance ; Surgery ; Tyrosine</subject><ispartof>PloS one, 2023-08, Vol.18 (8), p.e0289083</ispartof><rights>Copyright: © 2023 Nozawa et al. 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subjects Analysis
Animal models
Animals
Biology and Life Sciences
Cell cycle
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Contraception
Contraceptives
CRISPR
Cyclin-dependent kinases
Deletion
Embryos
Engineering and Technology
Exons
Fecundity
Female
Females
Fertility
Fertility - genetics
Frameshift mutation
Gametocytes
Health aspects
Histology
Humans
In vitro fertilization
Infertility
Kinases
Litter size
Medicine
Medicine and Health Sciences
Meiosis
Mice
Mutation
Oocytes
Oocytes - metabolism
Ovaries
Ovulation
Phenotypes
Phosphorylation
Prophase
Protein interaction
Protein Kinases - metabolism
Protein-protein interactions
Protein-tyrosine kinase
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
Proteins
Research and Analysis Methods
Statistical significance
Surgery
Tyrosine
title Oocyte-specific Wee1-like protein kinase 2 is dispensable for fertility in mice
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