| 1. |
- Adhikari, Deepak, et al.
(författare)
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Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:11, s. 2476-2484
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Adhikari, Deepak, et al.
(författare)
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Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:3, s. 397-410
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Reddy, Pradeep, et al.
(författare)
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Mechanisms maintaining the dormancy and survival of mammalian primordial follicles
- 2010
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Ingår i: Trends in endocrinology and metabolism. - : Elsevier BV. - 1043-2760 .- 1879-3061. ; 21:2, s. 96-103
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Zhang, Hua, et al.
(författare)
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Combating ovarian aging depends on the use of existing ovarian follicles, not on putative oogonial stem cells
- 2013
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Ingår i: Reproduction. - : Bioscientifica. - 1470-1626 .- 1741-7899. ; 146:6
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian aging is characterized by both a reduction in egg quality and a drastic reduction in the number of ovarian follicles. It has been generally accepted for 60 years that a fixed population of primordial follicles is established in the ovaries during early life, and in most mammalian species, oocytes cannot renew themselves in postnatal or adult life. This dogma, however, has been challenged over the past decade. In this review, we summarize the recent studies on primordial follicles and putative oogonial stem cells and discuss what resources in the ovary might be more reliable and promising source tools for combating ovarian aging.
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| 5. |
- Zhang, Hua, et al.
(författare)
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Experimental evidence showing that no mitotically active female germline progenitors exist in postnatal mouse ovaries
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 109:31, s. 12580-12585
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Tidskriftsartikel (refereegranskat)abstract
- It has been generally accepted for more than half a century that, in most mammalian species, oocytes cannot renew themselves in postnatal or adult life, and that the number of oocytes is already fixed in fetal or neonatal ovaries. This assumption, however, has been challenged over the past decade. In this study, we have taken an endogenous genetic approach to this question and generated a multiple fluorescent Rosa26(rbw/+); Ddx4-Cre germline reporter mouse model for in vivo and in vitro tracing of the development of female germline cell lineage. Through live cell imaging and de novo folliculogenesis experiments, we show that the Ddx4-expressing cells from postnatal mouse ovaries did not enter mitosis, nor did they contribute to oocytes during de novo folliculogenesis. Our results provide evidence that supports the traditional view that no postnatal follicular renewal occurs in mammals, and no mitotically active Ddx4-expressing female germline progenitors exist in postnatal mouse ovaries.
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| 6. |
- Zheng, Wenjing
(författare)
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Determine the developmental dynamics of primordial follicles in the mouse ovary
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian follicles are the basic functional units of the mammalian ovary. Progressive activation of primordial follicles serves as the source of fertilizable ova. In this thesis, by generating the Foxl2-CreERT2 and Sohlh1-CreERT2 mouse models, I have specifically labeled and traced the in vivo development of two classes of primordial follicles, the first wave of primordial follicles that are activated immediately after they are formed and the adult primordial follicles that are activated gradually in later life. The time-lapse tracing study has shown that the first wave of primordial follicles exist in the ovaries for about 3 months and contribute to the onset of puberty and to early fertility, whereas the adult primordial follicles gradually replace the first wave and dominate the ovary after 3 months of age, providing fertility until the end of reproductive life. Moreover, the two follicle populations also exhibit diverged minimal and maximal in vivo ripening times. Thus the two classes of primordial follicles follow distinct, age-dependent developmental paths and play different roles in the mammalian reproductive lifespan. Next I have verified whether primordial follicles can be regenerated from the purported female germline stem cells in the postnatal mouse ovary. We have created a multiple fluorescent Rosa26rbw/+;Ddx4-Cre germline reporter mouse model for in vivo and in vitro tracing the development of female germline cell lineage. Through live cell imaging and neo-folliculogenesis experiments, we have shown that the Ddx4-expressing cells from postnatal mouse ovaries do not divide during the in vitro culture, nor do they differentiate into oocytes following transplantation into the recipient mouse. Such experimental evidence supports the classic view that there is neither follicular replenishment nor female germline stem cell in the postnatal mammalian ovary. In summary, I have determined the developmental dynamics of two distinct populations of primordial follicles in the mouse ovary and confirmed that there is no spontaneous follicle regeneration. Such knowledge will hopefully lead to a more in-depth understanding of how different types of primordial follicles contribute to physiological and pathological alterations of the mammalian ovary.
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| 7. |
- Zheng, Wenjing, et al.
(författare)
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Functional roles of the phosphatidylinositol 3-kinases (PI3Ks) signaling in the mammalian ovary
- 2012
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207 .- 1872-8057. ; 356:1-2, s. 24-30
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Forskningsöversikt (refereegranskat)abstract
- Phosphatidylinositol 3-kinase (PI3K) signaling is a fundamental pathway for the regulation of cell proliferation, survival, migration, and metabolism in a variety of physiological and pathological processes. In recent years information provided by genetically modified mouse models has revealed that PI3K signaling plays vital roles in oogenesis, folliculogenesis, ovulation, and carcinogenesis in mouse ovary. In this review, we summarize (1) the physiological function of intra-oocyte PI3K signaling in regulation of primordial follicle survival and activation; (2) intra-granulosa cell PI3K signaling in regulation of cyclic follicular recruitment and ovulation; (3) intra-oocyte PI3K signaling in regulation of meiosis resumption and early embryogenesis; and also (4) the pathological function of PI3K signaling in ovarian diseases such as premature ovarian failure, granulosa cell tumors, and ovarian surface epithelium carcinomas. This updated info hopefully will lead to a better understanding of the human ovary and provide potential therapies for treating human infertility. © 2011.
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| 8. |
- Zheng, Wenjing, et al.
(författare)
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Maternal phosphatidylinositol 3-kinase signalling is crucial for embryonic genome activation and preimplantation embryogenesis
- 2010
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Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 11:11, s. 890-895
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
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| 10. |
- Zheng, Wenjing, et al.
(författare)
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The two classes of primordial follicles in the mouse ovary: their development, physiological functions and implications for future research
- 2014
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Ingår i: Molecular Human Reproduction. - : Oxford University Press (OUP). - 1360-9947 .- 1460-2407. ; 20:4, s. 286-292
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Forskningsöversikt (refereegranskat)abstract
- Ovarian follicles are the basic functional units in the mammalian ovary. This review summarizes early pioneering studies and focuses on recent progress that has shown that there are two distinct classes of primordial follicles in the ovary: the first wave of primordial follicles that are activated immediately after they are formed and the adult primordial follicles that are activated gradually in later life. These two separate classes have been proposed for two decades, but sufficient experimental evidence to support this hypothesis has only been obtained recently using newly developed follicular tracing techniques in genetically modified mouse models. These two follicle populations differ from each other primarily in terms of their developmental dynamics and their contributions to ovarian physiology. It is apparent now that these two follicle populations should be treated separately, and such knowledge will hopefully lead to a more in-depth understanding of how distinct types of primordial follicles contribute to physiologic and pathologic alterations of the mammalian ovary.
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| 11. |
- Zheng, Wenjing, et al.
(författare)
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Two classes of ovarian primordial follicles exhibit distinct developmental dynamics and physiological functions.
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:4, s. 920-928
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Tidskriftsartikel (refereegranskat)abstract
- In the mammalian ovary, progressive activation of primordial follicles serves as the source of fertilizable ova, and disorders in the development of primordial follicles lead to various ovarian diseases. However, very little is known about the developmental dynamics of primordial follicles under physiological conditions, and the fates of distinct populations of primordial follicles also remain unclear. In this study, by generating the Foxl2-CreERT2 and Sohlh1-CreERT2 inducible mouse models, we have specifically labeled and traced the in vivo development of two classes of primordial follicles, the first wave of simultaneously activated follicles after birth and the primordial follicles that are gradually activated in adulthood. Our results show that the first wave of follicles exists in the ovaries for ∼3 months and contributes to the onset of puberty and to early fertility. The primordial follicles at the ovarian cortex gradually replace the first wave of follicles and dominate the ovary after 3 months of age, providing fertility until the end of reproductive life. Moreover, by tracing the time periods needed for primordial follicles to reach various advanced stages in vivo, we were able to determine the exact developmental dynamics of the two classes of primordial follicles. We have now revealed the lifelong developmental dynamics of ovarian primordial follicles under physiological conditions and have clearly shown that two classes of primordial follicles follow distinct, age-dependent developmental paths and play different roles in the mammalian reproductive lifespan.
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