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Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden)
Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden)
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2012 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 11, 2476-2484 p.Article in journal (Refereed) Published
Abstract [en]

Mammalian oocytes are arrested at the prophase of meiosis I during fetal or postnatal development, and the meiosis is resumed by the preovulatory surge of luteinizing hormone. The in vivo functional roles of cyclin-dependent kinases (Cdks) during the resumption of meiosis in mammalian oocytes are largely unknown. Previous studies have shown that deletions of Cdk3, Cdk4 or Cdk6 in mice result in viable animals with normal oocyte maturation, indicating that these Cdks are not essential for the meiotic maturation of oocytes. In addition, conventional knockout of Cdk1 and Cdk2 leads to embryonic lethality and postnatal follicular depletion, respectively, making it impossible to study the functions of Cdk1 and Cdk2 in oocyte meiosis. In this study, we generated conditional knockout mice with oocyte-specific deletions of Cdk1 and Cdk2. We showed that the lack of Cdk1, but not of Cdk2, leads to female infertility due to a failure of the resumption of meiosis in the oocyte. Re-introduction of Cdk1 mRNA into Cdk1-null oocytes largely resumed meiosis. Thus, Cdk1 is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. We also found that Cdk1 maintains the phosphorylation status of protein phosphatase 1 and lamin A/C in oocytes in order for meiosis resumption to occur.

Place, publisher, year, edition, pages
2012. Vol. 21, no 11, 2476-2484 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-56192DOI: 10.1093/hmg/dds061ISI: 000304053100008OAI: oai:DiVA.org:umu-56192DiVA: diva2:532867
Available from: 2012-06-12 Created: 2012-06-12 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Signaling pathways in the development of female germ cells
Open this publication in new window or tab >>Signaling pathways in the development of female germ cells
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primordial follicles are the first small follicles to appear in the mammalian ovary. Women are born with a fixed number of primordial follicles in the ovaries. Once formed, the pool of primordial follicles serves as a source of developing follicles and oocytes. The first aim of this thesis was to investigate the functional role of the intra-oocyte signaling pathways, especially the phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin complex 1 (mTORC1) pathways in the regulation of primordial follicle activation and survival. We found that a primordial follicle remains dormant when the PI3K and mTORC1 signaling in its oocyte is activated to an appropriate level, which is just sufficient to maintain its survival, but not sufficient for its growth initiation. Hyperactivation of either of these signaling pathways causes global activation of the entire pool of primordial follicles leading to the exhaustion of all the follicles in young adulthood in mice. Mammalian oocytes, while growing within the follicles, remain arrested at prophase I of meiosis. Oocytes within the fully-grown antral follicles resume meiosis upon a preovulatory surge of leutinizing hormone (LH), which indicates that LH mediates the resumption of meiosis. The prophase I arrest in the follicle-enclosed oocyte is the result of low maturation promoting factor (MPF) activity, and resumption of meiosis upon the arrival of hormonal signals is mediated by activation of MPF. MPF is a complex of cyclin dependent kinase 1 (Cdk1) and cyclin B1, which is essential and sufficient for entry into mitosis. Although much of the mitotic cell cycle machinery is shared during meiosis, lack of Cdk2  in mice leads to a postnatal loss of all oocytes, indicating that Cdk2 is important for oocyte survival, and probably oocyte meiosis also. There have been conflicting results earlier about the role of Cdk2 in metaphase II arrest of Xenopus  oocytes. Thus the second aim of the thesis was to identify the specific Cdk that is essential for mouse oocyte meiotic maturation. We generated mouse models with oocytespecific deletion of Cdk1  or Cdk2  and studied the specific requirements of Cdk1 and Cdk2 during resumption of oocyte meiosis. We found that only Cdk1 is essential and sufficient for the oocyte meiotic maturation. Cdk1 does not only phosphorylate the meiotic phosphoproteins during meiosis resumption but also phosphorylates and suppresses the downstream protein phosphatase 1, which is essential for protecting the Cdk1 substrates from dephosphorylation.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2014. 41 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1649
Keyword
ovary, primordial follicle, activation, mTORC₁, PI₃K, oocyte maturation, MPF, Cdk₁
National Category
Biochemistry and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-88309 (URN)978-91-7601-056-3 (ISBN)
Public defence
2014-05-23, KB3B1, KBC-huset, Linnaeus väg 6, Umeå, 09:30 (English)
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Available from: 2014-04-30 Created: 2014-04-30 Last updated: 2014-05-05Bibliographically approved

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Adhikari, DeepakGorre, Nagaraju
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