Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) follicular signalling is conserved in the mare ovary

Sally E. Hall A B E , Rose M. O. Upton A , Eileen A. McLaughlin A C and Jessie M. Sutherland A D
+ Author Affiliations
- Author Affiliations

A Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Life Sciences Building, University of Newcastle, Callaghan, NSW 2308, Australia.

B Invasive Animals Cooperative Research Centre, Building 22, University of Canberra, Bruce, ACT 2617, Australia.

C School of Biological Sciences, Thomas Building, University of Auckland, Auckland 1010, New Zealand.

D Pregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.

E Corresponding author. Email: sally.e.hall@uon.edu.au

Reproduction, Fertility and Development 30(4) 624-633 https://doi.org/10.1071/RD17024
Submitted: 20 January 2017  Accepted: 3 September 2017   Published: 26 September 2017

Abstract

The mare ovary is unique in its anatomical structure; however, the signalling pathways responsible for physiological processes, such as follicular activation, remain uncharacterised. This provided us with the impetus to explore whether signalling molecules from important folliculogenesis pathways, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT), are conserved in the mare ovary. Messenger RNA expression of six genes important in follicle development was measured using quantitative polymerase chain reaction and protein localisation of key pathway members (PI3K, AKT1, phosphatase and tensin homologue (PTEN), JAK1, STAT3 and suppressor of cytokine signalling 4 (SOCS4)) was compared in tissue from fetal and adult mare ovaries. Tissue from adult ovaries exhibited significantly increased levels of mRNA expression of PI3K, AKT1, PTEN, JAK1, STAT3 and SOCS4 compared with tissue from fetal ovaries. PI3K, AKT1, JAK1 and STAT3 demonstrated redistributed localisation, from pregranulosa cells in fetal development, to both the oocyte and granulosa cells of follicles in the adult ovary, whilst negative feedback molecules PTEN and SOCS4 were only localised to the granulosa cells in the adult ovary. These findings suggest that the PI3K/AKT and JAK/STAT signalling pathways are utilised during folliculogenesis in the mare, similarly to previously studied mammalian species, and may serve as useful biomarkers for assessment of ovary development in the horse.

Additional keywords: biomarker, folliculogenesis, primordial follicle.


References

Adhikari, D., and Liu, K. (2009). Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocr. Rev. 30, 438–464.
Molecular mechanisms underlying the activation of mammalian primordial follicles.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtFaisbnO&md5=3aea20c5bfa10b987e7949f1d2081b3cCAS |

Adhikari, D., Gorre, N., Risal, S., Zhao, Z., Zhang, H., Shen, Y., and Liu, K. (2012). The safe use of a PTEN inhibitor for the activation of dormant mouse primordial follicles and generation of fertilizable eggs. PLoS One 7, e39034.
The safe use of a PTEN inhibitor for the activation of dormant mouse primordial follicles and generation of fertilizable eggs.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xps1Ojtrg%3D&md5=66add1bc04a368eabb635e40685b34baCAS |

Alves, K. A., Alves, B. G., Gastal, G. D., de Tarso, S. G., Gastal, M. O., Figueiredo, J. R., Gambarini, M. L., and Gastal, E. L. (2016). The mare model to study the effects of ovarian dynamics on preantral follicle features. PLoS One 11, e0149693.
The mare model to study the effects of ovarian dynamics on preantral follicle features.Crossref | GoogleScholarGoogle Scholar |

Aurich, C. (2011). Reproductive cycles of horses. Anim. Reprod. Sci. 124, 220–228.
Reproductive cycles of horses.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXlvFWhtbk%3D&md5=59de34a564069e736ba8af009551e30dCAS |

Bayne, R. A. L., Kinnell, H. L., Coutts, S. M., He, J., Childs, A. J., and Anderson, R. A. (2015). GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript. PLoS One 10, e0119819.
GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript.Crossref | GoogleScholarGoogle Scholar |

Bergin, W. C. (1968). ‘Developmental Horizons and Measurements Useful for Age Determination of Equine Embryos and Fetuses’. (Kansas State University: Manhattan.)

Carnevale, E. M. (2008). The mare model for follicular maturation and reproductive aging in the woman. Theriogenology 69, 23–30.
The mare model for follicular maturation and reproductive aging in the woman.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhsVSmu7nN&md5=0dbf159e52a30014bcd249e420f168b3CAS |

Childs, A. J., Kinnell, H. L., Collins, C. S., Hogg, K., Bayne, R. A. L., Green, S. J., McNeilly, A. S., and Anderson, R. A. (2010). BMP signaling in the human fetal ovary is developmentally regulated and promotes primordial germ cell apoptosis. Stem Cells 28, 1368–1378.
BMP signaling in the human fetal ovary is developmentally regulated and promotes primordial germ cell apoptosis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtF2ksrfK&md5=33a13ceadf678a783e53585b4076da60CAS |

Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., and Porcu, S. (2001). The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat. Genet. 27, 159–166.
The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXhtFGktLs%3D&md5=5b82ac8e1994c5ac578a0f7bfd82a724CAS |

Franciolli, A. L. R., Cordeiro, B. M., da Fonseca, E. T., Rodrigues, M. N., Sarmento, C. A. P., Ambrosio, C. E., de Carvalho, A. F., Miglino, M. A., and Silva, L. A. (2011). Characteristics of the equine embryo and fetus from days 15 to 107 of pregnancy. Theriogenology 76, 819–832.
Characteristics of the equine embryo and fetus from days 15 to 107 of pregnancy.Crossref | GoogleScholarGoogle Scholar |

Ginther, O. J. (2012). The mare: a 1000-pound guinea pig for study of the ovulatory follicular wave in women. Theriogenology 77, 818–828.
The mare: a 1000-pound guinea pig for study of the ovulatory follicular wave in women.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XivFOmtr0%3D&md5=4764900ae4d49a8a85ddd7cd71dcb9d0CAS |

Ginther, O. J., Gastal, E. L., Gastal, M. O., Bergfelt, D. R., Baerwald, A. R., and Pierson, R. A. (2004). Comparative study of the dynamics of follicular waves in mares and women. Biol. Reprod. 71, 1195–1201.
Comparative study of the dynamics of follicular waves in mares and women.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXnvVGqtLo%3D&md5=75a9fb54a9e71ccb2c05b02b5a47f3dfCAS |

Ginther, O. J., Beg, M. A., Gastal, E. L., Gastal, M. O., Baerwald, A. R., and Pierson, R. A. (2005). Systemic concentrations of hormones during the development of follicular waves in mares and women: a comparative study. Reproduction 130, 379–388.
Systemic concentrations of hormones during the development of follicular waves in mares and women: a comparative study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXhtFWisr3E&md5=574e24e87a7ff37d7e23666a808129f3CAS |

Hall, S. E., Nixon, B., and Aitken, R. J. (2017). Non-surgical sterilisation methods may offer a sustainable solution to feral horse (Equus caballus) overpopulation. Reprod. Fertil. Dev. 29, 1655–1666.
Non-surgical sterilisation methods may offer a sustainable solution to feral horse (Equus caballus) overpopulation.Crossref | GoogleScholarGoogle Scholar |

Huntriss, J., Lu, J., Hemmings, K., Bayne, R., Anderson, R., Rutherford, A., Balen, A., Elder, K., and Picton, H. M. (2017). Isolation and expression of the human gametocyte-specific factor 1 gene (GTSF1) in fetal ovary, oocytes, and preimplantation embryos. J. Assist. Reprod. Genet. 34, 23–31.
Isolation and expression of the human gametocyte-specific factor 1 gene (GTSF1) in fetal ovary, oocytes, and preimplantation embryos.Crossref | GoogleScholarGoogle Scholar |

Hutt, K. J., McLaughlin, E. A., and Holland, M. K. (2006a). KIT/KIT ligand in mammalian oogenesis and folliculogenesis: roles in rabbit and murine ovarian follicle activation and oocyte growth. Biol. Reprod. 75, 421–433.
KIT/KIT ligand in mammalian oogenesis and folliculogenesis: roles in rabbit and murine ovarian follicle activation and oocyte growth.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XovVWmurw%3D&md5=0406f264d466301492a70b8dd4ac562bCAS |

Hutt, K. J., McLaughlin, E. A., and Holland, M. K. (2006b). Primordial follicle activation and follicular development in the juvenile rabbit ovary. Cell Tissue Res. 326, 809–822.
Primordial follicle activation and follicular development in the juvenile rabbit ovary.Crossref | GoogleScholarGoogle Scholar |

Jagarlamudi, K., Liu, L., Adhikari, D., Reddy, P., Idahl, A., Ottander, U., Lundin, E., and 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, e6186.
Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation.Crossref | GoogleScholarGoogle Scholar |

John, G. B., Gallardo, T. D., Shirley, L. J., and Castrillon, D. H. (2008). Foxo3 is a PI3K-dependent molecular switch controlling the initiation of oocyte growth. Dev. Biol. 321, 197–204.
Foxo3 is a PI3K-dependent molecular switch controlling the initiation of oocyte growth.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtVSgtLzL&md5=97eb556f06bd0cb4eb53e0be3674720eCAS |

John, G. B., Shidler, M. J., Besmer, P., and Castrillon, D. H. (2009). Kit signaling via PI3K promotes ovarian follicle maturation but is dispensable for primordial follicle activation. Dev. Biol. 331, 292–299.
Kit signaling via PI3K promotes ovarian follicle maturation but is dispensable for primordial follicle activation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXpt1Wmur8%3D&md5=019497dc8610270687a9d876dfdd9a5bCAS |

Kerr, P. J., Jackson, R. J., Robinson, A. J., Swan, J., Silvers, L., French, N., Clarke, H., Hall, D. F., and Holland, M. K. (1999). Infertility in female rabbits (Oryctolagus cuniculus) alloimmunized with the rabbit zona pellucida protein ZPB either as a purified recombinant protein or expressed by recombinant myxoma virus. Biol. Reprod. 61, 606–613.
Infertility in female rabbits (Oryctolagus cuniculus) alloimmunized with the rabbit zona pellucida protein ZPB either as a purified recombinant protein or expressed by recombinant myxoma virus.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXlsFCqsLo%3D&md5=0d6bf316f780027f98dd4976ce68ba73CAS |

Kim, S. Y., Ebbert, K., Cordeiro, M. H., Romero, M., Zhu, J., Serna, V. A., Whelan, K. A., Woodruff, T. K., and Kurita, T. (2015). Cell autonomous phosphoinositide 3-kinase activation in oocytes disrupts normal ovarian function through promoting survival and overgrowth of ovarian follicles. Endocrinology 156, 1464–1476.
Cell autonomous phosphoinositide 3-kinase activation in oocytes disrupts normal ovarian function through promoting survival and overgrowth of ovarian follicles.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXls1Kltb8%3D&md5=faa5d6e3c8e22536debeef1c38b394e8CAS |

Lee, J.-J., Kim, B. C., Park, M.-J., Lee, Y.-S., Kim, Y.-N., Lee, B. L., and Lee, J.-S. (2011). PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation. Cell Death Differ. 18, 666–677.
PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXjtVCks7o%3D&md5=79bf4c36e916d2d2bc612f898abe75f6CAS |

Liu, L., Rajareddy, S., Reddy, P., Du, C., Jagarlamudi, K., Shen, Y., Gunnarsson, D., Selstam, G., Boman, K., and Liu, K. (2007). Infertility caused by retardation of follicular development in mice with oocyte-specific expression of FOXO3A. Development 134, 199–209.
Infertility caused by retardation of follicular development in mice with oocyte-specific expression of FOXO3A.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhsFaqt7o%3D&md5=421fb3e6142bb7d40107cd76d9b810ecCAS |

McCue, P. M. (1998). Review of ovarian abnormalities in the mare. In ‘Proceedings of the Annual Convention of the AAEP, Vol. 44’. pp. 125–33. (Ft. Collins, Colarado)

McEntee, M. (2012). ‘Reproductive Pathology of Domestic Mammals’. (Elsevier: San Diego.)

McLaughlin, E. A., and McIver, S. C. (2009). Awakening the oocyte: controlling primordial follicle development. Reproduction 137, 1–11.
Awakening the oocyte: controlling primordial follicle development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXovVKgsL4%3D&md5=aee7720b6056108987e1d543682cc00aCAS |

McLaughlin, M., Kinnell, H. L., Anderson, R. A., and Telfer, E. E. (2014). Inhibition of phosphatase and tensin homologue (PTEN) in human ovary in vitro results in increased activation of primordial follicles but compromises development of growing follicles. Mol. Hum. Reprod. 20, 736–744.
Inhibition of phosphatase and tensin homologue (PTEN) in human ovary in vitro results in increased activation of primordial follicles but compromises development of growing follicles.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXht1Clt7%2FJ&md5=2daa460e15a6be79a42f839e98608ee4CAS |

Ndiaye, K., Castonguay, A., Benoit, G., Silversides, D. W., and Lussier, J. G. (2016). Differential regulation of Janus kinase 3 (JAK3) in bovine preovulatory follicles and identification of JAK3 interacting proteins in granulosa cells. J. Ovarian Res. 9, 71.
Differential regulation of Janus kinase 3 (JAK3) in bovine preovulatory follicles and identification of JAK3 interacting proteins in granulosa cells.Crossref | GoogleScholarGoogle Scholar |

Nilsson, E. E., Kezele, P., and Skinner, M. K. (2002). Leukemia inhibitory factor (LIF) promotes the primordial to primary follicle transition in rat ovaries. Mol. Cell. Endocrinol. 188, 65–73.
Leukemia inhibitory factor (LIF) promotes the primordial to primary follicle transition in rat ovaries.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XitFWntrw%3D&md5=c320cdb43b17d4be0a4e61ade556eaa2CAS |

Ono, M., Akuzawa, H., Nambo, Y., Hirano, Y., Kimura, J., Takemoto, S., Nakamura, S., Yokota, H., Himeno, R., Higuchi, T., Ohtaki, T., and Tsumagari, S. (2015). Analysis of the equine ovarian structure during the first twelve months of life by three-dimensional internal structure microscopy. J. Vet. Med. Sci. 77, 1599–1603.
Analysis of the equine ovarian structure during the first twelve months of life by three-dimensional internal structure microscopy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC28Xoslertbo%3D&md5=eb375e7d09143d3a9f1b1d76e20a8dbaCAS |

Pan, L., Gong, W., Zhou, Y., Li, X., Yu, J., and Hu, S. (2014). A comprehensive transcriptomic analysis of infant and adult mouse ovary. Genomics Proteomics Bioinformatics 12, 239–248.
A comprehensive transcriptomic analysis of infant and adult mouse ovary.Crossref | GoogleScholarGoogle Scholar |

Pastuschek, J., Poetzsch, J., Morales-Prieto, D. M., Schleußner, E., Markert, U. R., and Georgiev, G. (2015). Stimulation of the JAK/STAT pathway by LIF and OSM in the human granulosa cell line COV434. J. Reprod. Immunol. 108, 48–55.
Stimulation of the JAK/STAT pathway by LIF and OSM in the human granulosa cell line COV434.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXlt1aisLg%3D&md5=e03b6d278725ba2d21ff11d69385aba2CAS |

Pisarska, M. D., Bae, J., Klein, C., and Hsueh, A. J. (2004). Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinology 145, 3424–3433.
Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXltFyktrs%3D&md5=d6749c4bd9cb75f3c6f1b94a7d94f531CAS |

Platt, H. (1978). Growth and maturity in the equine fetus. J. R. Soc. Med. 71, 658–661.
Growth and maturity in the equine fetus.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaE1M%2FltVCjsw%3D%3D&md5=67df3aad5d90c3f18cab5d3fd0255923CAS |

Reddy, P., Liu, L., Adhikari, D., Jagarlamudi, K., Rajareddy, S., Shen, Y., Du, C., Tang, W., Hämäläinen, T., and Peng, S. L. (2008). Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science 319, 611–613.
Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXht1Knt78%3D&md5=f1d3ecbc7771c8c70e4569bc3ebaaba3CAS |

Sakai, T. (1955). Studies on the development of the embryonic ovary in swine, cattle and horse. Jpn. J. Vet. Res. 3, 183–194.

Sarraj, M. A., and Drummond, A. E. (2012). Mammalian foetal ovarian development: consequences for health and disease. Reproduction 143, 151–163.
Mammalian foetal ovarian development: consequences for health and disease.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xjs1Kkt7w%3D&md5=d7484b1e40bf1aff7517ce20f9e5eb5fCAS |

Schauer, S. N., Sontakke, S. D., Watson, E. D., Esteves, C. L., and Donadeu, F. X. (2013). Involvement of miRNAs in equine follicle development. Reproduction 146, 273–282.
Involvement of miRNAs in equine follicle development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhsVaiu77E&md5=31af8267d3795b80b1ad7a510895f430CAS |

Schmid, A. C., Byrne, R. D., Vilar, R., and Woscholski, R. (2004). Bisperoxovanadium compounds are potent PTEN inhibitors. FEBS Lett. 566, 35–38.
Bisperoxovanadium compounds are potent PTEN inhibitors.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXktVOlt70%3D&md5=705c25567be783ea01f6264fa37c9d6dCAS |

Sobinoff, A. P., Sutherland, J. M., and Mclaughlin, E. A. (2013a). Intracellular signalling during female gametogenesis. Mol. Hum. Reprod. 19, 265–278.
Intracellular signalling during female gametogenesis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXmtlChtL0%3D&md5=a88844c4f7d3bdc66cfa756755c11ce0CAS |

Sobinoff, A. P., Beckett, E. L., Jarnicki, A. G., Sutherland, J. M., McCluskey, A., Hansbro, P. M., and McLaughlin, E. A. (2013b). Scrambled and fried: cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress. Toxicol. Appl. Pharmacol. 271, 156–167.
Scrambled and fried: cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXht1aqsLrI&md5=86ff8c59c346d728e4b6575260994f7dCAS |

Sutherland, J. M., Keightley, R., Robker, R. L., Russell, D. L., and McLaughlin, E. A. (2010). JAK/STAT signalling in folliculogenesis. Reprod. Fertil. Dev. 22, 44.
JAK/STAT signalling in folliculogenesis.Crossref | GoogleScholarGoogle Scholar |

Sutherland, J. M., Keightley, R. A., Nixon, B., Roman, S. D., Robker, R. L., Russell, D. L., and McLaughlin, E. A. (2012). Suppressor of cytokine signaling 4 (SOCS4): moderator of ovarian primordial follicle activation. J. Cell. Physiol. 227, 1188–1198.
Suppressor of cytokine signaling 4 (SOCS4): moderator of ovarian primordial follicle activation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhs1GhtLnF&md5=42a30bc7a2969d9455fe47eed488a03bCAS |

Tuck, A. R., Robker, R. L., Norman, R. J., Tilley, W. D., and Hickey, T. E. (2015). Expression and localisation of c-kit and KITL in the adult human ovary. J. Ovarian Res. 8, 31.
Expression and localisation of c-kit and KITL in the adult human ovary.Crossref | GoogleScholarGoogle Scholar |

Uhlenhaut, N. H., and Treier, M. (2006). Foxl2 function in ovarian development. Mol. Genet. Metab. 88, 225–234.
Foxl2 function in ovarian development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xms1agu7Y%3D&md5=34a76a7a0384632b1d9d80f2128859deCAS |

Wang, L.-Q., Liu, J.-C., Chen, C.-L., Cheng, S.-F., Sun, X.-F., Zhao, Y., Yin, S., Hou, Z.-M., Pan, B., Ding, C., Shen, W., and Zhang, X.-F. (2016). Regulation of primordial follicle recruitment by cross-talk between the Notch and phosphatase and tensin homologue (PTEN)/AKT pathways. Reprod. Fertil. Dev. 28, 700–712.
Regulation of primordial follicle recruitment by cross-talk between the Notch and phosphatase and tensin homologue (PTEN)/AKT pathways.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC28XmsFOlsb0%3D&md5=e6c9385de54487785fcd4d5a1528444fCAS |

Yoshikawa, K., Nigorikawa, K., Tsukamoto, M., Tamura, N., Hazeki, K., and Hazeki, O. (2007). Inhibition of PTEN and activation of Akt by menadione. Biochim. Biophys. Acta 1770, 687–693.
Inhibition of PTEN and activation of Akt by menadione.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXit1Ggsbg%3D&md5=52586adf85454afb3ee29cdc6c27e56bCAS |

Zhang, H., Risal, S., Gorre, N., Busayavalasa, K., Li, X., Shen, Y., Bosbach, B., Brannstrom, M., and Liu, K. (2014). Somatic cells initiate primordial follicle activation and govern the development of dormant oocytes in mice. Curr. Biol. 24, 2501–2508.
Somatic cells initiate primordial follicle activation and govern the development of dormant oocytes in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhvVantbvL&md5=74d7bbdd20ae668bbd64c5c9943f7293CAS |

Zheng, W., Nagaraju, G., Liu, Z., and Liu, K. (2012). Functional roles of the phosphatidylinositol 3-kinases (PI3Ks) signaling in the mammalian ovary. Mol. Cell. Endocrinol. 356, 24–30.
Functional roles of the phosphatidylinositol 3-kinases (PI3Ks) signaling in the mammalian ovary.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xls1egs7Y%3D&md5=4a7c2daa726cd8ca03d0e06ce8e6c7b1CAS |