p27kip1 (Cyclin-Dependent Kinase Inhibitor 1B) Controls Ovarian Development by Suppressing Follicle Endowment and Activation and Promoting Follicle Atresia in Mice

Abstract In humans, the molecular mechanisms underlying ovarian follicle endowment and activation, which are closely related to the control of female reproduction, occurrence of menopause, and related diseases such as premature ovarian failure, are poorly understood. In the current study, we provide several lines of genetic evidence that the cyclin-dependent kinase (Cdk) inhibitor 1B (commonly known as p27kip1 or p27) controls ovarian development in mice by suppressing follicle endowment and activation, and by promoting follicle death. In p27-deficient (p27−/−) mice, postnatal follicle assembly was accelerated, and the number of endowed follicles was doubled as compared with p27+/+ mice. Moreover, in p27−/− ovaries the primordial follicle pool was prematurely activated once it was endowed, and at the same time the massive follicular death that occurs before sexual maturity was rescued by loss of p27. In early adulthood, however, the overactivated follicular pool in p27−/− ovaries was largely depleted, causing premature ovarian failure. Furthermore, we have extensively studied the molecular mechanisms underlying the above-mentioned phenotypes seen in p27−/− ovaries and have found that p27 controls follicular development by several distinct mechanisms at different stages of development of the ovary. For example, p27 controls oocyte growth by suppressing the functions of Cdk2/Cdc2-cyclin A/E1 in oocytes that are arrested at the diplotene stage of meiosis I. This function of p27 is distinct from its well-known role as a suppressor of cell cycle progression. In addition, we have found that p27 activates the caspase-9-caspase-3-caspase-7-poly (ADP-ribose) polymeraseapoptotic cascade by inhibiting Cdk2/Cdc2-cyclin A/B1 kinase activities in follicles, thereby inducing follicle atresia. Our results suggest that the p27 gene is important in determining mammalian ovarian development. This study therefore provides insight into ovary-borne genetic aberrations that cause defects in folliculogenesis and infertility in humans.

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Analysis of cyclin-dependent kinase inhibitor 1B mutation in Han Chinese women with premature ovarian failure

Reproductive BioMedicine Online ◽

10.1016/j.rbmo.2010.04.025 ◽

2010 ◽

Vol 21 (2) ◽

pp. 212-214 ◽

Cited By ~ 6

Author(s):

Binbin Wang ◽

Feng Ni ◽

Lin Li ◽

Zhaolian Wei ◽

Xianglong Zhu ◽

...

Keyword(s):

Premature Ovarian Failure ◽

Kinase Inhibitor ◽

Chinese Women ◽

Ovarian Failure ◽

Han Chinese ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor

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Ablation of beta subunit of protein kinase CK2 in mouse oocytes causes follicle atresia and premature ovarian failure

Cell Death and Disease ◽

10.1038/s41419-018-0505-1 ◽

2018 ◽

Vol 9 (5) ◽

Cited By ~ 2

Author(s):

Qiu-Xia Liang ◽

Zhen-Bo Wang ◽

Fei Lin ◽

Chun-Hui Zhang ◽

Hong-Mei Sun ◽

...

Keyword(s):

Protein Kinase ◽

Premature Ovarian Failure ◽

Protein Kinase Ck2 ◽

Ovarian Failure ◽

Beta Subunit ◽

Mouse Oocytes ◽

Follicle Atresia ◽

Kinase Ck2

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The Roles of Different Stem Cells in Premature Ovarian Failure

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190314123006 ◽

2020 ◽

Vol 15 (6) ◽

pp. 473-481 ◽

Cited By ~ 2

Author(s):

Cheng Zhang

Keyword(s):

Stem Cells ◽

Premature Ovarian Failure ◽

Treatment Method ◽

Ovarian Failure ◽

Female Reproduction ◽

Regeneration Potential ◽

Signaling Mechanisms ◽

Stem Cells Therapy ◽

Ovarian Structure ◽

And Function

Premature ovarian failure (POF) is characterized by amenorrhea, hypergonadotropism and hypoestrogenism before the age of 40, which affects 1% of women in the general population. POF is complex and heterogeneous due to its pathogenetic mechanisms. It is one of the significant causes of female infertility. Although many treatments are available for POF, these therapies are less efficient and trigger many side effects. Therefore, to find effective therapeutics for POF is urgently required. Due to stem cells having self-renewal and regeneration potential, they may be effective for the treatment of ovarian failure and consequently infertility. Recent studies have found that stem cells therapy may be able to restore the ovarian structure and function in animal models of POF and provide an effective treatment method. The present review summarizes the biological roles and the possible signaling mechanisms of the different stem cells in POF ovary. Further study on the precise mechanisms of stem cells on POF may provide novel insights into the female reproduction, which not only enhances the understanding of the physiological roles but also supports effective therapy for recovering ovarian functions against infertility.

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Very low doses of heavy oxygen ion radiation induce premature ovarian failure

Reproduction ◽

10.1530/rep-17-0101 ◽

2017 ◽

Vol 154 (2) ◽

pp. 123-133 ◽

Cited By ~ 9

Author(s):

Birendra Mishra ◽

Ryan Ripperdan ◽

Laura Ortiz ◽

Ulrike Luderer

Keyword(s):

Premature Ovarian Failure ◽

Ovarian Follicle ◽

Charged Particles ◽

Primordial Follicle ◽

Ovarian Follicles ◽

Ovarian Failure ◽

Space Travel ◽

Dna Double Strand Breaks ◽

Cancer Radiotherapy ◽

Early Effects

Astronauts are exposed to charged particles during space travel, and charged particles are also used for cancer radiotherapy. Premature ovarian failure is a well-known side effect of conventional, low linear energy transfer (LET) cancer radiotherapy, but little is known about the effects of high LET charged particles on the ovary. We hypothesized that lower LET (16.5 keV/µm) oxygen particles would be less damaging to the ovary than we previously found for iron (LET = 179 keV/µm). Adult female mice were irradiated with 0, 5, 30 or 50 cGy oxygen ions or 50 cGy oxygen plus dietary supplementation with the antioxidant alpha lipoic acid (ALA). Six-hour after irradiation, percentages of ovarian follicles immunopositive for γH2AX, a marker of DNA double strand breaks, 4-HNE, a marker of oxidative lipid damage and BBC3 (PUMA), a proapoptotic BCL-2 family protein, were dose dependently increased in irradiated mice compared to controls. One week after irradiation, numbers of primordial, primary and secondary follicles per ovary were dose dependently decreased, with complete absence of follicles in the 50 cGy groups. The ED50 for primordial follicle destruction was 4.6 cGy for oxygen compared to 27.5 cGy for iron in our previous study. Serum FSH and LH concentrations were significantly elevated in 50 cGy groups at 8 week. Supplementation with ALA mitigated the early effects, but not the ultimate depletion of ovarian follicles. In conclusion, oxygen charged particles are even more potent inducers of ovarian follicle depletion than charged iron particles, raising concern for premature ovarian failure in astronauts exposed to both particles during space travel.

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Expression of Pluripotency and Oocyte-Related Genes in Single Putative Stem Cells from Human Adult Ovarian Surface Epithelium CulturedIn Vitroin the Presence of Follicular Fluid

BioMed Research International ◽

10.1155/2013/861460 ◽

2013 ◽

Vol 2013 ◽

pp. 1-18 ◽

Cited By ~ 17

Author(s):

Irma Virant-Klun ◽

Thomas Skutella ◽

Mikael Kubista ◽

Andrej Vogler ◽

Jasna Sinkovec ◽

...

Keyword(s):

Stem Cells ◽

Cell Cultures ◽

Follicular Fluid ◽

Premature Ovarian Failure ◽

Ovarian Surface Epithelium ◽

Ovarian Failure ◽

Reproductive Hormones ◽

Surface Epithelium ◽

Oocyte Growth ◽

Ovarian Surface

The aim of this study was to trigger the expression of genes related to oocytes in putative ovarian stem cells scraped from the ovarian surface epithelium of women with premature ovarian failure and culturedin vitroin the presence of follicular fluid, rich in substances for oocyte growth and maturation. Ovarian surface epithelium was scraped and cell cultures were set up by scrapings in five women with nonfunctional ovaries and with no naturally present mature follicles or oocytes. In the presence of donated follicular fluid putative stem cells grew and developed into primitive oocyte-like cells. A detailed single-cell gene expression profiling was performed to elucidate their genetic status in comparison to human embryonic stem cells, oocytes, and somatic fibroblasts. The ovarian cell cultures depleted/converted reproductive hormones from the culture medium. Estradiol alone or together with other substances may be involved in development of these primitive oocyte-like cells. The majority of primitive oocyte-like cells was mononuclear and expressed several genes related to pluripotency and oocytes, including genes related to meiosis, although they did not express some important oocyte-specific genes. Our work reveals the presence of putative stem cells in the ovarian surface epithelium of women with premature ovarian failure.

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Amniotic Fluid Stem Cells Prevent Follicle Atresia and Rescue Fertility of Mice with Premature Ovarian Failure Induced by Chemotherapy

PLoS ONE ◽

10.1371/journal.pone.0106538 ◽

2014 ◽

Vol 9 (9) ◽

pp. e106538 ◽

Cited By ~ 43

Author(s):

Guan-Yu Xiao ◽

I-Hsuan Liu ◽

Chun-Chun Cheng ◽

Chia-Chun Chang ◽

Yen-Hua Lee ◽

...

Keyword(s):

Stem Cells ◽

Amniotic Fluid ◽

Premature Ovarian Failure ◽

Ovarian Failure ◽

Amniotic Fluid Stem Cells ◽

Follicle Atresia

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Association of an APBA3 Missense Variant with Risk of Premature Ovarian Failure in the Korean Female Population

Journal of Personalized Medicine ◽

10.3390/jpm10040193 ◽

2020 ◽

Vol 10 (4) ◽

pp. 193

Author(s):

JeongMan Park ◽

YoungJoon Park ◽

Insong Koh ◽

Nam Keun Kim ◽

Kwang-Hyun Baek ◽

...

Keyword(s):

Cell Proliferation ◽

Candidate Genes ◽

Premature Ovarian Failure ◽

Complex Disease ◽

Ovarian Follicle ◽

Additive Model ◽

Missense Variant ◽

Ovarian Failure ◽

Female Population ◽

Medicine Research

Premature ovarian failure (POF) is a complex disease of which the etiology is influenced by numerous genetic variations. Several POF candidate genes have been reported. However, no causal genes with high odds ratio (OR) have yet been discovered. This study included 564 females of Korean ethnicity, comprising 60 patients with POF and 182 controls in the discovery set and 105 patients with POF and 217 controls in the replication set. We conducted genome-wide association analysis to search for novel candidate genes predicted to influence POF development using Axiom Precision Medicine Research Arrays and additive model logistic regression analysis. One statistically significant single nucleotide polymorphism (SNP), rs55941146, which encodes a missense alteration (Val > Gly) in the APBA3 gene, was identified with OR values for association with POF of 13.33 and 4.628 in the discovery and replication sets, respectively. No rs55941146 minor allele homozygotes were present in either cases or controls. The APBA3 protein binds FIH-1 that inhibits hypoxia inducible factor-1α (HIF-1α). HIF-1α contributes to granulosa cell proliferation, which is crucial for ovarian follicle growth, by regulating cell proliferation factors and follicle stimulating hormone-mediated autophagy. Our data demonstrate that APBA3 is a candidate novel causal gene for POF.

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