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Liu, Kui
Publications (10 of 31) Show all publications
Jagarlamudi, K., Reddy, P., Adhikari, D. & Liu, K. (2010). Genetically modified mouse models for premature ovarian failure (POF). Molecular and Cellular Endocrinology, 315(1-2), 1-10
Open this publication in new window or tab >>Genetically modified mouse models for premature ovarian failure (POF)
2010 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 315, no 1-2, p. 1-10Article in journal (Refereed) Published
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.

Keywords
Premature ovarian failure (POF); Mouse models; Ovary; Follicular development
Identifiers
urn:nbn:se:umu:diva-42925 (URN)10.1016/j.mce.2009.07.016 (DOI)000274608900001 ()19643165 (PubMedID)
Available from: 2011-04-14 Created: 2011-04-14 Last updated: 2018-06-08Bibliographically approved
Zheng, W., Gorre, N., Shen, Y., Noda, T., Ogawa, W., Lundin, E. & Liu, K. (2010). Maternal phosphatidylinositol 3-kinase signalling is crucial for embryonic genome activation and preimplantation embryogenesis. EMBO Reports, 11(11), 890-895
Open this publication in new window or tab >>Maternal phosphatidylinositol 3-kinase signalling is crucial for embryonic genome activation and preimplantation embryogenesis
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2010 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 11, no 11, p. 890-895Article in journal (Refereed) Published
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.

Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-46368 (URN)10.1038/embor.2010.144 (DOI)000283507900016 ()20930845 (PubMedID)
Available from: 2011-08-31 Created: 2011-08-31 Last updated: 2018-06-08Bibliographically approved
Reddy, P., Zheng, W. & Liu, K. (2010). Mechanisms maintaining the dormancy and survival of mammalian primordial follicles. Trends in endocrinology and metabolism, 21(2), 96-103
Open this publication in new window or tab >>Mechanisms maintaining the dormancy and survival of mammalian primordial follicles
2010 (English)In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 21, no 2, p. 96-103Article in journal (Refereed) Published
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.

Identifiers
urn:nbn:se:umu:diva-42924 (URN)10.1016/j.tem.2009.10.001 (DOI)000275156800006 ()19913438 (PubMedID)
Available from: 2011-04-14 Created: 2011-04-14 Last updated: 2018-06-08Bibliographically approved
Adhikari, D. & Liu, K. (2010). mTOR signaling in the control of activation of primordial follicles. Cell Cycle, 9(9), 1673-1674
Open this publication in new window or tab >>mTOR signaling in the control of activation of primordial follicles
2010 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 9, no 9, p. 1673-1674Article in journal (Refereed) Published
Keywords
mTORC1, primordial follicle activation, fertility preservation
Identifiers
urn:nbn:se:umu:diva-42923 (URN)10.4161/cc.9.9.11626 (DOI)20404510 (PubMedID)
Available from: 2011-04-14 Created: 2011-04-14 Last updated: 2018-06-08Bibliographically approved
Adhikari, D., Zheng, W., Shen, Y., Gorre, N., Hämäläinen, T., Cooney, A. J., . . . Liu, K. (2010). Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Human Molecular Genetics, 19(3), 397-410
Open this publication in new window or tab >>Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles
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2010 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 3, p. 397-410Article in journal (Refereed) Published
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.

Identifiers
urn:nbn:se:umu:diva-42927 (URN)10.1093/hmg/ddp483 (DOI)000273227200001 ()19843540 (PubMedID)
Available from: 2011-04-14 Created: 2011-04-14 Last updated: 2018-06-08Bibliographically approved
Adhikari, D., Flohr, G., Gorre, N., Shen, Y., Yang, H., Lundin, E., . . . Liu, K. (2009). Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles. Molecular human reproduction, 15(12), 765-770
Open this publication in new window or tab >>Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles
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2009 (English)In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 15, no 12, p. 765-770Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Oxford University Press, 2009
National Category
Biophysics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-36336 (URN)10.1093/molehr/gap092 (DOI)19843635 (PubMedID)
Available from: 2010-09-28 Created: 2010-09-28 Last updated: 2018-06-08Bibliographically approved
Adhikari, D. & Liu, K. (2009). Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocrine reviews, 30(5), 438-464
Open this publication in new window or tab >>Molecular mechanisms underlying the activation of mammalian primordial follicles
2009 (English)In: Endocrine reviews, ISSN 0163-769X, E-ISSN 1945-7189, Vol. 30, no 5, p. 438-464Article in journal (Refereed) Published
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.

Identifiers
urn:nbn:se:umu:diva-42926 (URN)10.1210/er.2008-0048 (DOI)19589950 (PubMedID)
Available from: 2011-04-14 Created: 2011-04-14 Last updated: 2018-06-08Bibliographically approved
Jagarlamudi, K., Liu, L., Adhikari, D., Reddy, P., Idahl, A., Ottander, U., . . . Liu, K. (2009). Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation. PLoS ONE, 4(7), e6186
Open this publication in new window or tab >>Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation
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2009 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 7, p. e6186-Article in journal (Refereed) Published
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.

Identifiers
urn:nbn:se:umu:diva-26301 (URN)10.1371/journal.pone.0006186 (DOI)19587782 (PubMedID)
Available from: 2009-10-07 Created: 2009-10-05 Last updated: 2018-06-08Bibliographically approved
Dubbaka Venu, P. R., Adhikari, D., Zheng, W., Liang, S., Hämäläinen, T., Tohonen, V., . . . Liu, K. (2009). PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles. Human Molecular Genetics, 18(15), 2813-2824
Open this publication in new window or tab >>PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles
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2009 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 15, p. 2813-2824Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-26086 (URN)10.1093/hmg/ddp217 (DOI)19423553 (PubMedID)
Available from: 2009-09-28 Created: 2009-09-23 Last updated: 2018-06-08Bibliographically approved
Wahlberg, P., Nylander, A., Ahlskog, N., Liu, K. & Ny, T. (2008). Expression and localization of the serine proteases high-temperature requirement factor A1, serine protease 23, and serine protease 35 in the mouse ovary.. Endocrinology, 149(10), 5070-7
Open this publication in new window or tab >>Expression and localization of the serine proteases high-temperature requirement factor A1, serine protease 23, and serine protease 35 in the mouse ovary.
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2008 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 10, p. 5070-7Article in journal (Refereed) Published
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.

Identifiers
urn:nbn:se:umu:diva-22420 (URN)10.1210/en.2007-1736 (DOI)18566130 (PubMedID)
Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2018-06-08
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