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  • 1.
    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, p. 765-770Article 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.

  • 2.
    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, p. 438-464Article 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.

  • 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.
    mTOR signaling in the control of activation of primordial follicles2010In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 9, no 9, p. 1673-1674Article in journal (Refereed)
  • 4.
    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, p. 397-410Article 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.

  • 5.
    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, p. 2813-2824Article 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.

  • 6.
    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, p. 611-613Article in journal (Refereed)
  • 7.
    Fallah, Mahsa
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Viklund, Emil
    Shen, Yue
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bäckman, Assar
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundskog, Bertil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Blomqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wilczynska, Malgorzata
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Plasminogen enhances the healing of radiation-induced wounds via decreased expression of pro-inflammatory and pro-fibrotic factorsManuscript (preprint) (Other academic)
  • 8.
    Gunnarsson, David
    et al.
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Leffler, Per
    Umeå University, Faculty of Science and Technology, European CBRNE Center.
    Ekwurtzel, Emelie
    Martinsson, Gunilla
    Liu, Kui
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Selstam, Gunnar
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes2008In: Reproduction, ISSN 1470-1626, E-ISSN 1476-3990, Vol. 135, no 5, p. 693-703Article in journal (Refereed)
    Abstract [en]

    Phthalates are widely used as plasticizers in a number of daily-life products. In this study, we investigated the influence of mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of the frequently used plasticizer di-(2-ethylhexyl) phthalate (DEHP), on gonadal steroidogenesis in vitro. MEHP (25–100 µM) stimulated basal steroid synthesis in a concentration-dependent manner in immortalized mouse Leydig tumor cells (MLTC-1). The stimulatory effect was also detected in KK-1 granulosa tumor cells. MEHP exposure did not influence cAMP or StAR protein levels and induced a gene expression profile of key steroidogenic proteins different from the one induced by human chorionic gonadotropin (hCG). Simultaneous treatment with MEHP and a p450scc inhibitor (aminoglutethimide) indicated that MEHP exerts its main stimulatory effect prior to pregnenolone formation. MEHP (10–100 µM) up-regulated hormone-sensitive lipase and 3-hydroxy-3-methylglutaryl coenzyme A reductase, suggesting that MEHP increases the amount of cholesterol available for steroidogenesis. Our data suggest that MEHP, besides its known inhibitory effect on hCG action, can directly stimulate gonadal steroidogenesis in both sexes through a cAMP- and StAR-independent mechanism. The anti-steroidogenic effect of DEHP has been proposed to cause developmental disorders such as hypospadias and cryptorchidism, whereas a stimulation of steroid synthesis may prematurely initiate the onset of puberty and theoretically affect the hypothalamic–pituitary–gonadal axis.

  • 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, p. e6186-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, p. 1-10Article 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.

  • 11.
    Liu, Kui
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Stem cell factor (SCF)-kit mediated phosphatidylinositol2006In: Frontiers in bioscience, ISSN 1093-4715, p. 126-35Article in journal (Refereed)
  • 12.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Stem cell factor (SCF)-kit mediated phosphatidylinositol 3 (PI3) kinase signaling during mammalian oocyte growth and early follicular development.2006In: Frontiers in bioscience : a journal and virtual library, ISSN 1093-4715, Vol. 11, p. 126-35Article, review/survey (Other academic)
    Abstract [en]

    The bi-directional communication between mammalian oocytes and their surrounding granulosa cells has been shown to be crucial for ovarian follicular development. Studies on molecules derived from the oocytes, such as growth differentiation factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15), have attracted great interest during the past decade, and it is common knowledge nowadays that these molecules participate in the bi-directional dialogue between the oocytes and their surrounding granulosa cells as well as follicular development. However, signaling molecules and pathways inside mammalian oocytes that control oocyte growth and early development of ovarian follicles, which may be monitored by factors produced by granulosa cells, have not been studied extensively. Based on our own data as well as ovarian phenotypes observed in several gene modified mice strains that were generated for studies of signal transduction, immunology and cancer, the current review focuses on the key features of the activation of oocyte phosphatidylinositol 3 kinase (PI3 kinase) pathway and its possible roles during mammalian oocyte growth and follicular development. We propose that the cascade from the granulosa cell-produced stem cell factor (SCF) to the oocyte surface SCF receptor Kit, and to the oocyte PI3 kinase pathway, may play an important role in the regulation of growth rate of mammalian oocytes, as well as in the activation and development of ovarian follicles.

  • 13.
    Liu, Kui
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Olofsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlberg, Patrik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Distinct expression ofgelatinase A (MMP-2), collagenase-3 (MMP-13), membrane-type MMP 1 (MT1-MMP), and tissue inhibitor of MMPs type 1 (TIMP-1) mediated by physiological signals during formation and regression of the rat corpus luteum1999In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 140, no 11, p. 5330-5338Article in journal (Refereed)
    Abstract [en]

    The corpus luteum (CL) is a transient endocrine organ that secretes progesterone to support pregnancy. The CL is formed from an ovulated follicle in a process that involves extensive angiogenesis and tissue remodeling. If fertilization does not occur or implantation is unsuccessful, the CL will undergo regression, which involves extensive tissue degradation. Extracellular proteases, such as serine proteases and matrix metalloproteinases (MMPs), are thought to play important roles in both the formation and regression of the CL. In this study, we have examined the physiological regulation pattern and cellular distribution of messenger RNAs coding for gelatinase A (MMP-2), collagenase-3 (MMP-13), membrane type MMP 1 (MT1-MMP, MMP-14), and the major MMP inhibitor, tissue inhibitor of MMPs type 1 (TIMP-1) in the CL of adult pseudopregnant (psp) rat. Northern blot and in situ hybridization analyses revealed that gelatinase A messenger RNA was mainly expressed during luteal development, indicating that gelatinase A may be associated with the neovascularization and tissue remodeling that takes place during CL formation. Collagenase-3 had a separate expression pattern and was only expressed in the regressing CL, suggesting that this MMP may be related with luteal regression. MT1-MMP that in vitro can activate progelatinase A and procollagenase-3 was constitutively expressed during the formation, function, and regression of the CL and may therefore be involved in the activation of these MMPs. TIMP-1 was induced during both the formation and regression of the CL, suggesting that this inhibitor modulates MMP activity during these processes. To test whether the induction of collagenase-3 and TIMP-1 is coupled with luteal regression, we prolonged the luteal phase by performing hysterectomies, and induced premature luteal regression by treating the pseudopregnant rats with a PGF2alpha analog, cloprostenol. In both treatments, collagenase-3 and TIMP-1 were induced only after the serum level of progesterone had decreased, suggesting that collagenase-3 and TIMP-1 are induced by physiological signals, which initiate functional luteolysis to play a role in tissue degradation during structural luteolysis. In conclusion, our data suggest that gelatinase A, collagenase-3, and MT1-MMP may have separate functions during the CL life span: gelatinase A mainly takes part in CL formation, whereas collagenase-3 mainly takes part in luteal regression; MT1-MMP is constitutively expressed during the CL life span and may therefore serve as an in vivo activator of both gelatinase A and collagenase-3. TIMP-1 is up-regulated both during the formation and regression of the CL and may therefore regulate MMP activity during both processes.

  • 14.
    Liu, Kui
    et al.
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Rajareddy, Singareddy
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Liu, Lian
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Jagarlamudi, Krishna
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Boman, Karin
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Selstam, Gunnar
    Molecular Biology (Faculty of Medicine).
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Control of mammalian oocyte growth and early follicular development by the oocyte PI3 kinase pathway: new roles for an old timer2006In: Dev Biol, ISSN 0012-1606, Vol. 299, no 1, p. 1-11Article in journal (Refereed)
  • 15.
    Liu, Kui
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wahlberg, Patrik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hägglund, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Expression pattern and functional studies of matrix degrading proteases and their inhibitors in the mouse corpus luteum2003In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 205, no 1-2, p. 131-140Article in journal (Refereed)
    Abstract [en]

    The formation of the corpus luteum (CL) is accompanied with angiogenesis and tissue remodeling and its regression involves tissue degradation. Matrix degrading proteases such as plasminogen activators (PAs) and matrix metalloproteinases (MMPs) are thought to play important roles in such controlled proteolytic processes. In this study, in situ hybridization has been used to examine the regulation and expression pattern of mRNAs coding for proteases and protease inhibitors belonging to the PA- and MMP-systems during the life cycle of the CL in an adult pseudopregnant mouse model. Of the nine proteases and five protease inhibitors that were studied, the majority were found to be temporally expressed during the formation and/or the regression of the CL. However, the mRNAs coding for urokinase type PA (uPA), membrane-type 1 MMP (MT1-MMP), and tissue inhibitor of metalloproteinases type-3 (TIMP-3) were constantly expressed in the mouse CL throughout its whole life span. To study the functional role of uPA in the CL, we analyzed luteal formation and function in uPA deficient mice. Our results revealed no significant difference in ovarian weight, serum progesterone levels, and blood vessel density in the functional CL between uPA deficient and wild type control mice. The temporal and spatial expression pattern of proteases and protease inhibitors during the CL life span suggests that members of the PA- and MMP-systems may play important roles in the angiogenesis and tissue remodeling processes during CL formation, as well as in the tissue degradation during luteal regression. However, the absence of reproductive phenotypes in mice lacking uPA and several other matrix degrading proteases indicates that there are redundancies among different matrix degrading proteases or that tissue remodeling in the ovary may involve other additional unique elements.

  • 16.
    Liu, Kui
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wahlberg, Patrik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Leonardsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hägglund, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Annelii
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bodén, Ida
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wibom, Carin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lund, Leif R
    Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Successful ovulation in plasminogen-deficient mice treated with the broad-spectrum matrix metalloproteinase inhibitor galardin.2006In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 295, no 2, p. 615-622Article in journal (Refereed)
    Abstract [en]

    Many studies have suggested the hypothesis that the plasminogen activator (PA) system and the matrix metalloproteinase (MMP) system, either separately or in combination, may provide the proteolytic activity that is required for rupture of the follicular wall at the time of ovulation. Our recent studies on ovulation in plasminogen (plg)-deficient mice have, however, shown that plasmin is not required for normal ovulation, leading us to the hypothesis that MMPs may be a more important source of proteolysis for this process. To investigate the role of MMPs and also the possibility of a functional overlap or synergy between the MMP and PA systems during ovulation, we have studied ovulation efficiency in wild-type and plg-deficient mice treated with the broad-spectrum MMP inhibitor galardin. We found that in both wild-type mice and heterozygous plg-deficient (plg(+/-)) mice that had been treated with galardin prior to ovulation, there was a mild (18-20%) reduction in ovulation efficiency. Surprisingly, galardin treatment of plg-deficient (plg(-/-)) mice only caused an additional 14% reduction in ovulation efficiency as compared to vehicle-treated plg(-/-) mice. Our data therefore suggest that although MMPs may play a role in degradation of the follicular wall, they may not be obligatory for ovulation. In contrast to previous studies on tissue remodeling during wound heating and placental development, we have demonstrated that there is no obvious functional overlap or synergy between the PA and MMP systems, which has previously been thought to be essential for the ovulatory process.

  • 17.
    Liu, Kui
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wahlberg, Patrik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Coordinated and cell-specific regulation of membrane-type matrix metalloproteinase 1 (MT1-MMP) and its substrate matrix metalloproteinase 2 (MMP-2) by physiological signals during follicular development and ovulation1998In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 139, no 11, p. 4735-4738Article in journal (Refereed)
    Abstract [en]

    In the ovary, extensive tissue remodeling is required during both follicular development and the break down of the follicular wall at the time of ovulation. Extracellular proteases such as serine proteases and matrix metalloproteinases (MMPs) are thought to play pivotal roles in these processes. In this paper, we have used in situ hybridization to study the regulation and distribution of mRNA coding for MMP-2 (gelatinase A) and its cell surface activator membrane-type MMP1 (MT1-MMP) during gonadotropin induced ovulation in the rat. In ovaries of untreated immature (23 day old) rats, the levels of MT1-MMP and MMP-2 mRNA were low. MMP-2 mRNA was found in theca-interstitial cells while MT1-MMP mRNA was found in both granulosa and theca-interstitial cells and both messages were induced after stimulation with PMSG. After an ovulatory dose of hCG, the expression of MT1-MMP was dramatically down regulated in the granulosa cell layers of large preovulatory follicles but the expression remained and appeared to be up regulated together with MMP-2 in the theca-interstitial cells surrounding the large preovulatory follicles. The expression kinetics and tissue distribution supports the notion that MT1-MMP may have dual functions in the ovary. Initially MT1-MMP may act as a matrix degrading protease inside the follicle during follicular development and later, just prior to ovulation, as an activator of proMMP-2 in theca-interstitial cells surrounding preovulatory follicles.

  • 18.
    Liu, Lian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rajareddy, Singareddy
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Du, Chun
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Jagarlamudi, Krishna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Yan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gunnarsson, David
    Selstam, Gunnar
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Boman, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a2007In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 134, no 1, p. 199-209Article in journal (Refereed)
    Abstract [en]

    In recent years, mammalian oocytes have been proposed to have important roles in the orchestration of ovarian follicular development and fertility. To determine whether intra-oocyte Foxo3a, a component of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, influences follicular development and female fertility, a transgenic mouse model was generated with constitutively active Foxo3a expressed in oocytes. We found that the female transgenic mice were infertile, which was caused by retarded oocyte growth and follicular development, and anovulation. Further mechanistic studies revealed that the constitutively active Foxo3a in oocytes caused a dramatic reduction in the expression of bone morphogenic protein 15 (Bmp15), connexin 37 and connexin 43, which are important molecules for the establishment of paracrine and gap junction communications in follicles. Foxo3a was also found to facilitate the nuclear localization of p27(kip1) in oocytes, a cyclin-dependent kinase (Cdk) inhibitor that may serve to inhibit oocyte growth. The results from the current study indicate that Foxo3a is an important intra-oocyte signaling molecule that negatively regulates oocyte growth and follicular development. Our study may therefore give some insight into oocyte-borne genetic aberrations that cause defects in follicular development and anovulation in human diseases, such as premature ovarian failure.

  • 19. Liu, Lian
    et al.
    Rajareddy, Singareddy
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Jagarlamudi, Krishna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Du, Chun
    Shen, Yan
    Guo, Yongzhi
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Boman, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lundin, Eva
    Patologi.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Selstam, Gunnar
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development.2007In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 38, no 1-2, p. 137-146Article in journal (Refereed)
    Abstract [en]

    Communication between mammalian oocytes and their surrounding granulosa cells through the Kit-Kit ligand (KL, or stem cell factor, SCF) system has been shown to be crucial for follicular development. Our previous studies (Reddy et al. 2005, Liu et al. 2006) have indicated that the intra-oocyte KL-Kit-PI3 kinase (PI3K)-Akt-Foxo3a cascade may play an important role in follicular activation and early development. In the present study, using in situ hybridization and in vitro culture of growing oocytes from 8-day-old postnatal mice, we have demonstrated that another Akt substrate, glycogen synthase kinase-3 (GSK-3), is expressed in growing oocytes. Also, treatment of cultured mouse oocytes with soluble KL not only leads to increased Akt kinase activity in the oocytes, which can phosphorylate recombinant GSK-3 in vitro, but also leads to phosphorylation of oocyte GSK-3alpha and GSK-3beta, which can result in the inactivation of GSK-3 function in oocytes. In addition, we have shown that the regulation of GSK-3alpha and GSK-3beta in cultured oocytes by soluble KL is accomplished through PI3K, since the PI3K-specific inhibitor LY294002 completely abolished the KL-induced phosphorylation of GSK-3alpha and GSK-3beta. Moreover, blockage of the Kit signaling pathway by a Kit function-blocking antibody, ACK2, resulted in reduced phosphorylation of GSK-3. Taken together, our data suggest that the cascade from granulosa cell-derived KL to Kit-PI3K-Akt-GSK-3 in oocytes may take part in regulation of oocyte growth and early ovarian follicular development.

  • 20. Liu, Yi-Xun
    et al.
    Liu, Kui
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Feng, Qiang
    Hu, Zhao-Yuan
    Liu, Hai-Zhen
    Fu, Guo-Qing
    Li, Yin-Chuan
    Zou, Ru-Jin
    Ny, Tor
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Tissue-type plasminogen activator and its inhibitor plasminogen activator inhibitor type 1 are coordinately expressed during ovulation in the rhesus monkey.2004In: Endocrinology, ISSN 0013-7227, Vol. 145, no 4, p. 1767-75Article in journal (Refereed)
  • 21.
    Ottander, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hosokawa, Kenichi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Olofsson, Jan I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    A putative stimulatory role of progesterone acting via progesterone receptors in the steroidogenic cells of the human corpus luteum2000In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 62, no 3, p. 655-663Article in journal (Refereed)
    Abstract [en]

    To further explore the proposed auto-regulatory role of progesterone action in the human corpus luteum (CL), the expression and functional roles of progesterone receptor (PR) isoforms A and B during the luteal phase (LP) of the menstrual cycle were investigated. A total of 27 otherwise healthy patients previously scheduled for surgery were recruited after informed consent. An LH rise was detected, and CL were grouped according to age (Days 2-5 post-LH-rise, early LP; Days 6-10, mid LP; Days 11-14, late LP). Using a semiquantitative reverse transcription-polymerase chain reaction assay, the PR-B mRNA levels, which were 100- to 1000-fold lower than PR-A/B mRNA, were 46% lower (P < 0.05, n = 24) in mid LP, compared to early and late LP. CL tissue levels of progesterone and PR-A/B protein levels were inversely correlated to increasing CL age; i.e., significantly reduced levels were observed in the late LP (r(2) = 0.34, P < 0.01, n = 23). Expression of PR-A/B mRNA as well as PR-A/B protein were detected by in situ hybridization and immunohistochemistry, respectively. Both methods revealed a clear and distinct localization to cells in the steroidogenic layer of the CL. Freshly obtained mid-luteal CL cells were cultured in vitro, and media were analyzed for progesterone concentrations after treatment by incremental doses of hCG and the stable PR antagonist mifepristone, alone or in combination. Mifepristone did not per se alter progesterone synthesis, but when it was added in conjunction with hCG, a dose-related inhibitory response was seen, with a maximal 47% reduction in progesterone output at a 10 microM addition (P < 0.05, n = 3). Collectively, these data implicate a stimulatory role of progesterone receptor-mediated action in the steroidogenic cells of the human CL, which may serve as an important pathway for maintaining functional homeostasis during early pregnancy.

  • 22.
    Rajareddy, Singareddy
    et al.
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Du, Chun
    Liu, Lian
    Jagarlamudi, Krishna
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Tang, Wenli
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Shen, Yan
    Berthet, Cyril
    Peng, Stanford L
    Kaldis, Philipp
    Liu, Kui
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    p27kip1 (cyclin-dependent kinase inhibitor 1B) controls ovarian development by suppressing follicle endowment and activation and promoting follicle atresia in mice2007In: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 21, no 9, p. 2189-2202Article in journal (Refereed)
  • 23.
    Reddy, Pradeep
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Lian
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ren, Chong
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lindgren, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Boman, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Shen, Yan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Rytinki, Miia
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Formation of E-cadherin-mediated cell-cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells2005In: Mol Endocrinol, ISSN 0888-8809, Vol. 19, no 10, p. 2564-2578Article in journal (Refereed)
  • 24.
    Reddy, Pradeep
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Lijun
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ren, Chong
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Boman, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindgren, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Liu, Yi-Xun
    Sun, Qing-Yuan
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development2005In: Dev Biol, ISSN 0012-1606, Vol. 281, no 2, p. 160-170Article in journal (Refereed)
  • 25.
    Reddy, Pradeep
    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.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mechanisms maintaining the dormancy and survival of mammalian primordial follicles2010In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 21, no 2, p. 96-103Article in journal (Refereed)
    Abstract [en]

    To preserve the length of a woman's reproductive life it is essential that the majority of her ovarian primordial follicles are maintained in a quiescent state to provide a reserve for continuous reproductive success. The mechanisms maintaining the dormancy and survival of primordial follicles have been a mystery for decades. In recent years information provided by genetically modified mouse models has revealed a number of molecules whose functions are indispensable for the maintenance of follicular quiescence (including PTEN, Tsc1, Tsc2, Foxo3a, p27) and survival (PI3K signaling). Here we summarize this updated information, which hopefully will lead to a better understanding of the pathophysiology of the human ovary and provide potential therapeutic options for some types of infertility.

  • 26. Sun, Qing-Yuan
    et al.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kikuchi, Kazuhiro
    Oocyte-specific knockout: a novel in vivo approach for studying gene functions during folliculogenesis, oocyte maturation, fertilization, and embryogenesis.2008In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 79, no 6, p. 1014-20Article in journal (Refereed)
    Abstract [en]

    Knockout mice have been highly useful tools in helping to understand the functional roles of specific genes in development and diseases. However, in many cases, knockout mice are embryonic lethal, which prevents investigation into a number of important questions, or they display developmental abnormalities, including fertility defects. In contrast, conditional knockout, which is achieved by the Cre-LoxP system, can be used to delete a gene in a specific organ or tissue, or at a specific developmental stage. This technique has advantages over conventional knockout, especially when conventional knockout causes embryonic lethality or when the function of maternal transcripts in early development needs to be defined. Recently, a widely used practice has been used to specifically delete genes of interest in oocytes: Zp3-Cre or Gdf9-Cre transgenic mouse lines, in which Cre-recombinase expression is driven by oocyte-specific zona pellucida 3 (Zp3) promoter or growth differentiation factor 9 (Gdf9) promoter, are crossed with mice bearing floxed target genes. This novel in vivo approach has helped to increase the understanding of the functions of specific genes in folliculogenesis/oogenesis, oocyte maturation, fertilization, and embryogenesis. In this minireview we discuss recent advances in understanding the molecular mechanisms regulating major reproductive and developmental events as revealed by oocyte-specific conditional knockout and perspectives on this technology and related studies.

  • 27.
    Wahlberg, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bodén, Ida
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Plasminogen is required for normal progesterone production in the mouseManuscript (Other academic)
  • 28.
    Wahlberg, Patrik
    et al.
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Bodén, Ida
    Paulsson, Josefin
    Lund, Leif R
    Liu, Kui
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Functional corpora lutea are formed in matrix metalloproteinase inhibitor-treated plasminogen-deficient mice.2007In: Endocrinology, ISSN 0013-7227, Vol. 148, no 3, p. 1226-34Article in journal (Refereed)
    Abstract [en]

    The extended Förster theory (EFT) is for the first time applied to the quantitative determination of the intramolecular distances in proteins. It is shown how the EFT (J. Chem. Phys., 1996, 105, 10896) can be adapted to the analyses of fluorescence depolarisation experiments based on the time-correlated single photon counting technique (TCSPC). The protein system studied was the latent form of plasminogen activator inhibitor type I (PAI-1), which was mutated and labelled by the thiol reactive BODIPY® derivative {N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-yl)methyl iodoacetamide}. The energy migration occurs within pairs of photophysically identical donor groups that undergo reorientational motions on the timescales of energy migration and fluorescence relaxation. Unlike all models currently used for analysing fluorescence TCSPC data, the EFT explicitly accounts for the time-dependent reorientations that influence the rate of electronic energy transfer/migration in a complex manner. The complexity is related to the 2 problem, which has been discussed for years. The EFT brings the analyses of DDEM data to the same level of molecular description as in ESR and NMR spectroscopy, i.e. it yields microscopic information about the reorientation correlation times, the order parameters, as well as inter-chromophoric distances.

  • 29.
    Wahlberg, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nylander, Asa
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ahlskog, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Expression and localization of the serine proteases high-temperature requirement factor A1, serine protease 23, and serine protease 35 in the mouse ovary.2008In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 10, p. 5070-7Article in journal (Refereed)
    Abstract [en]

    Proteolytic degradation of extracellular matrix components has been suggested to play an essential role in the occurrence of ovulation. Recent studies in our laboratory have indicated that the plasminogen activator and matrix metalloproteinase systems, which were previously believed to be crucial for ovulation, are not required in this process. In this study we have used a microarray approach to identify new proteases that are involved in ovulation. We found three serine proteases that were relatively highly expressed during ovulation: high-temperature requirement factor A1 (HtrA1), which was not regulated much during ovulation; serine protease 23 (PRSS23), which was down-regulated by gonadotropins; and serine protease 35 (PRSS35), which was up-regulated by gonadotropins. We have further investigated the expression patterns of these proteases during gonadotropin-induced ovulation in immature mice and in the corpus luteum (CL) of pseudopregnant mice. We found that HtrA1 was highly expressed in granulosa cells throughout follicular development and ovulation, as well as in the forming and regressing CL. PRSS23 was highly expressed in atretic follicles, and it was expressed in the ovarian stroma and theca tissues just before ovulation. PRSS35 was expressed in the theca layers of developing follicles. It was also highly induced in granulosa cells of preovulatory follicles. PRSS35 was also expressed in the forming and regressing CL. These data suggest that HtrA1 and PRSS35 may be involved in ovulation and CL formation and regression, and that PRSS23 may play a role in follicular atresia.

  • 30. Yu, Ling-Zhu
    et al.
    Xiong, Bo
    Gao, Wen-Xue
    Wang, Chun-Min
    Zhong, Zhi-Sheng
    Huo, Li-Jun
    Wang, Qiang
    Hou, Yi
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, X Johné
    Schatten, Heide
    Chen, Da-Yuan
    Sun, Qing-Yuan
    MEK1/2 regulates microtubule organization, spindle pole tethering and asymmetric division during mouse oocyte meiotic maturation.2007In: Cell cycle (Georgetown, Tex.), ISSN 1551-4005, Vol. 6, no 3, p. 330-8Article in journal (Refereed)
    Abstract [en]

    It is well known that MAPK plays pivotal roles in oocyte maturation, but the function of MEK (MAPK kinase) remains unknown. We have studied the expression, subcellular localization and functional roles of MEK during meiotic maturation of mouse oocytes. Firstly, we found that MEK1/2 phoshorylation (p-MEK1/2, indicative of MEK activation) was low in GV (germinal vesicle) stage, increased 2h after GVBD (germinal vesicle breakdown), and reached the maximum at metaphase II. Secondly, we found that P-MEK1/2 was restricted in the GV prior to GVBD. In prometaphase I and metaphase I, P-MEK1/2 was mainly associated with the spindle, especially with the spindle poles. At anaphase I and telophase I, p-MEK1/2 became diffusely distributed in the region between the separating chromosomes, and then became associated with the midbody. The association of p-MEK1/2 with spindle poles was further confirmed by its colocalization with the centrosomal proteins, gamma-tubulin and NuMA. Thirdly, we have investigated the possible functional role of MEK1/2 activation by intravenous administration and intrabursal injection of a specific MEK inhibitor, U0126, and by microinjection of MEK siRNA into oocytes. All these manipulations cause disorganized spindle poles and spindle structure, misaligned chromosomes and larger than normal polar bodies. Our results suggest that MEK1/2 may function as a centrosomal protein and may have roles in microtubule organization, spindle pole tethering and asymmetric division during mouse oocyte maturation.

  • 31.
    Zheng, Wenjing
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gorre, Nagaraju
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Yue
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Noda, Tetsuo
    Ogawa, Wataru
    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.
    Maternal phosphatidylinositol 3-kinase signalling is crucial for embryonic genome activation and preimplantation embryogenesis2010In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 11, no 11, p. 890-895Article in journal (Refereed)
    Abstract [en]

    Maternal effect factors derived from oocytes are important for sustaining early embryonic development before the major wave of embryonic genome activation (EGA). In this study, we report a two-cell-stage arrest of embryos lacking maternal 3-phosphoinositide-dependent protein kinase 1 as a result of suppressed EGA. Concurrent deletion of maternal Pten completely rescued the suppressed EGA and embryonic progression through restored AKT signalling, which fully restored the fertility of double-mutant females. Our study identifies maternal phosphatidylinositol 3-kinase signalling as a new maternal effect factor that regulates EGA and preimplantation embryogenesis in mice.

1 - 31 of 31
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