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  • 1.
    Adhikari, Deepak
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Signaling pathways in the development of female germ cells2014Doctoral 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.

  • 2.
    Adhikari, Deepak
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Flohr, Gilian
    Hogeschool Leiden, Zernikedreef 11,2333 CK Leiden, The Netherlands.
    Gorre, Nagaraju
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Yan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Yang, Hairu
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lan, Zijian
    University of Louisville Health Sciences Center, Louisville, Kentucky, USA.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles2009In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 15, no 12, 765-770 p.Article in journal (Refereed)
    Abstract [en]

    To maintain the length of reproductive life in a woman, it is essential that most of her ovarian primordial follicles are maintained in a quiescent state to provide a continuous supply of oocytes. However, our understanding of the molecular mechanisms that control the quiescence and activation of primordial follicles is still in its infancy. In this study, we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 (Tsc2), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the dormancy of primordial follicles. In mutant mice lacking the Tsc2 gene in oocytes, the pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in oocytes. This results in depletion of follicles in early adulthood, causing premature ovarian failure (POF). Our results suggest that the Tsc1-Tsc2 complex mediated suppression of mTORC1 activity is indispensable for maintenance of the dormancy of primordial follicles, thus preserving the follicular pool, and that mTORC1 activity in oocytes promotes follicular activation. Our results also indicate that deregulation of Tsc/mTOR signaling in oocytes may cause pathological conditions of the ovary such as infertility and POF.

  • 3.
    Adhikari, Deepak
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Molecular mechanisms underlying the activation of mammalian primordial follicles2009In: Endocrine reviews, ISSN 0163-769X, E-ISSN 1945-7189, Vol. 30, no 5, 438-464 p.Article in journal (Refereed)
    Abstract [en]

    In humans and other mammalian species, the pool of resting primordial follicles serves as the source of developing follicles and fertilizable ova for the entire length of female reproductive life. One question that has intrigued biologists is: what are the mechanisms controlling the activation of dormant primordial follicles. Studies from previous decades have laid a solid, but yet incomplete, foundation. In recent years, molecular mechanisms underlying follicular activation have become more evident, mainly through the use of genetically modified mouse models. As hypothesized in the 1990s, the pool of primordial follicles is now known to be maintained in a dormant state by various forms of inhibitory machinery, which are provided by several inhibitory signals and molecules. Several recently reported mutant mouse models have shown that a synergistic and coordinated suppression of follicular activation provided by multiple inhibitory molecules is necessary to preserve the dormant follicular pool. Loss of function of any of the inhibitory molecules for follicular activation, including PTEN (phosphatase and tensin homolog deleted on chromosome 10), Foxo3a, p27, and Foxl2, leads to premature and irreversible activation of the primordial follicle pool. Such global activation of the primordial follicle pool leads to the exhaustion of the resting follicle reserve, resulting in premature ovarian failure in mice. In this review, we summarize both historical and recent results on mammalian primordial follicular activation and focus on the up-to-date knowledge of molecular networks controlling this important physiological event. We believe that information obtained from mutant mouse models may also reflect the molecular machinery responsible for follicular activation in humans. These advances may provide a better understanding of human ovarian physiology and pathophysiology for future clinical applications.

  • 4.
    Adhikari, Deepak
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    mTOR signaling in the control of activation of primordial follicles2010In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 9, no 9, 1673-1674 p.Article in journal (Refereed)
  • 5.
    Adhikari, Deepak
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zheng, Wenjing
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Yan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gorre, Nagaraju
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hämäläinen, Tuula
    Cooney, Austin J
    Huhtaniemi, Ilpo
    Lan, Zi-Jian
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 3, 397-410 p.Article in journal (Refereed)
    Abstract [en]

    To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility.

  • 6.
    Adhikari, Deepak
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zheng, Wenjing
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Shen, Yan
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Gorre, Nagaraju
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ning, Yao
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Halet, Guillaume
    Univ Rennes 1, CNRS, UMR 6061, Inst Genet & Dev Rennes, F-35043 Rennes, France .
    Kaldis, Philipp
    NUS, A STAR, IMCB, Singapore 138673, Singapore.
    Liu, Kui
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes2012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 11, 2476-2484 p.Article in journal (Refereed)
    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.

  • 7.
    Dubbaka Venu, Pradeep Reddy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Adhikari, Deepak
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zheng, Wenjing
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liang, Shawn
    Hämäläinen, Tuula
    Tohonen, Virpi
    Ogawa, Wataru
    Noda, Tetsuo
    Volarevic, Sinisa
    Huhtaniemi, Ilpo
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles2009In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 15, 2813-2824 p.Article in journal (Refereed)
    Abstract [en]

    The molecular mechanisms that control reproductive aging and menopausal age in females are poorly understood. Here, we provide genetic evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) signaling in oocytes preserves reproductive lifespan by maintaining the survival of ovarian primordial follicles. In mice lacking the PDK1-encoding gene Pdk1 in oocytes, the majority of primordial follicles are depleted around the onset of sexual maturity, causing premature ovarian failure (POF) during early adulthood. We further showed that suppressed PDK1-Akt-p70 S6 kinase 1 (S6K1)-ribosomal protein S6 (rpS6) signaling in oocytes appears to be responsible for the loss of primordial follicles, and mice lacking the Rps6 gene in oocytes show POF similar to that in Pdk1-deficient mice. In combination with our earlier finding that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in oocytes suppresses follicular activation, we have now pinpointed the molecular network involving phosphatidylinositol 3 kinase (PI3K)/PTEN-PDK1 signaling in oocytes that controls the survival, loss and activation of primordial follicles, which together determine reproductive aging and the length of reproductive life in females. Underactivation or overactivation of this signaling pathway in oocytes is shown to cause pathological conditions in the ovary, including POF and infertility.

  • 8.
    Dubbaka Venu, Pradeep Reddy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Lian
    Adhikari, Deepak
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Jagarlamudi, Krishna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rajareddy, Singareddy
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Yan
    Du, Chun
    Tang, Wenli
    Hämäläinen, Tuula
    Peng, Stanford L
    Lan, Zi-Jian
    Cooney, Austin J
    Huhtaniemi, Ilpo
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool2008In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 319, no 5863, 611-613 p.Article in journal (Refereed)
  • 9.
    Jagarlamudi, Krishna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Lian
    Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University, Jinan, China.
    Adhikari, Deepak
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 7, e6186- p.Article in journal (Refereed)
    Abstract [en]

    Immature ovarian primordial follicles are essential for maintenance of the reproductive lifespan of female mammals. Recently, it was found that overactivation of the phosphatidylinositol 3-kinase (PI3K) signaling in oocytes of primordial follicles by an oocyte-specific deletion of Pten (phosphatase and tensin homolog deleted on chromosome ten), the gene encoding PI3K negative regulator PTEN, results in premature activation of the entire pool of primordial follicles, indicating that activation of the PI3K pathway in oocytes is important for control of follicular activation. To investigate whether PI3K signaling in oocytes of primary and further developed follicles also plays a role at later stages in follicular development and ovulation, we conditionally deleted the Pten gene from oocytes of primary and further developed follicles by using transgenic mice expressing zona pellucida 3 (Zp3) promoter-mediated Cre recombinase. Our results show that Pten was efficiently deleted from oocytes of primary and further developed follicles, as indicated by the elevated phosphorylation of the major PI3K downstream component Akt. However, follicular development was not altered and oocyte maturation was also normal, which led to normal fertility with unaltered litter size in the mutant mice. Our data indicate that properly controlled PTEN/PI3K-Akt signaling in oocytes is essential for control of the development of primordial follicles whereas overactivation of PI3K signaling in oocytes does not appear to affect the development of growing follicles. This suggests that there is a stage-specific function of PTEN/PI3K signaling in mouse oocytes that controls follicular activation.

  • 10.
    Jagarlamudi, Krishna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Adhikari, Deepak
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Genetically modified mouse models for premature ovarian failure (POF)2010In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 315, no 1-2, 1-10 p.Article in journal (Refereed)
    Abstract [en]

    Premature ovarian failure (POF) is a complex disorder that affects approximately 1% of women. POF is characterized by the depletion of functional ovarian follicles before the age of 40 years, and clinically, patients may present with primary amenorrhea or secondary amenorrhea. Although some genes have been hypothesized to be candidates responsible for POF, the etiology of most of the cases is idiopathic, with the underlying causes still unidentified because of the heterogeneity of the disease. In this review, we consider some mutant mouse models that exhibit phenotypes which are comparable to human POF, and we suggest that the use of these mouse models may help us to gain a better understanding of the molecular mechanisms underlying POF in humans.

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