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Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2012; 58(6): 89-97

Regulation of oocyte meiotic resumption in mammals

Shepel' OA, Blashkiv TV, Voznesens'ka TIu, Ianchiĭ RI

    O.O. Bogomolets Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine


Currently, the molecular mechanisms involved in induction of oocyte meiotic resumption in the pre-ovulatory follicle which may include (involve) the elimination of meiosis inhibiting factors and/or the accumulation or activation of oocyte matu­ration signals are actively studied. The present review sum­marizes the existing literature data regarding the participation of cyclic monophosphates (cAMP and cGMP), protein kinases (mitogen-activated protein kinase (MAPK), АІ, АІІ, В, С, G), epidermal-growth factors (EGF), EGF-like factors, mRNA EGF and EGF-like factors, ovarian steroid hormones and ste-rols, as well as transcription factors NF-kB and CREB (cAMP response element binding protein) in the regulation of mam­malian oocyte meiotic resumption. Such scheme of regulation of oocyte meiotic resumption is discussed (considered): the ac­tion of gonadotrophins, FSH and LH, causes increase the pro­duction of cAMP and subsequent activation of MAPK. cGMP (during follicular growth) can prevent untimely oocyte meiotic resumption up to ovulation (after LH surge, after increase in LH). FSH- and the LH -induced system of EGF, steroids and sterols are involved in MAPK activation. Whereas different FSH and LH effects on NO production in ovary are involved in the regulation of induction of oocyte meiotic resumption in mammals. The further research is needed to better understand the new important mechanisms that regulate diffcult aspects of oocyte meiotic maturation in mammals.

Keywords: oocyte, meiotic resumption, gonadotrophins,cyclic monophosphates, epidermal-growth factors, proteinkinases, steroids, sterols.


  1. Blashkiv T.V., Shepel' E.A., Voznesenskaya T.Yu. Vliyanie linolevoi kisloti i pirrolidin ditiokarbamata na meioticheskoe sozrevanie ootsitov i vizhivaemost' kletok ih kumulyusnogo okruzheniya . Probl. reproduktsii. 2012. 18, N 1. S. 17-20.
  3. Ashkenazi H., Cao X., Motola S., Popliker M., Conti M., Tsafriri A. Epidermal growth factor family members: endogenous mediators of the ovulatory response . Endocrinology. 2005. 146, N 1. P. 77-84. CrossRef PubMed
  5. Baltsen M. Gonadotropin-induced accumulation of 4,4-dimethylsterols in mouse ovaries and its temporal relation to meiosis . Biol. Reprod. 2001. 65, N 6. P. 1743-1750. CrossRef PubMed
  7. Bopassa J.C., Ferrera R., Gateau-Roesch O., Couture-Lepetit E., Ovize M. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning . Cardiovasc. Res. 2006. 69, N 1. P. 178 185. CrossRef PubMed
  9. Byskov A.G., Andersen C.Y., Leonardsen L. Role of meiosis activating sterols, MAS, in induced oocyte maturation . Mol. Cell Endocrinol. 2002. 187, N 1-2. P. 189-196. CrossRef  
  10. Chen X., Zhou B., Yan J., Xu B., Tai P., Li J., Peng S., Zhang M., Xia G. Epidermal growth factor receptor activation by protein kinase C is necessary for FSH-induced meiotic resumption in porcine cumulus-oocyte complexes . J. Endocrinol. 2008. 197, N 2. P. 409-419. CrossRef PubMed
  12. Chian R.C., Ao A., Clarke H.J., Tulandi T., Tan S.L. Production of steroids from human cumulus cells treated with different concentrations of gonadotropins during culture in vitro . Fertil. Steril. 1999. 71, N 1. P. 61-66. CrossRef  
  13. Conti M., Andersen C.B., Richard F., Mehats C., Chun S.Y., Horner K., Jin C., Tsafriri A. Role of cyclic nucleotide signaling in oocyte maturation . Mol. Cell Endocrinol. 2002. 187, N 1-2. P. 153-159. CrossRef  
  14. Cukurcam S., Hegele-Hartung C., Eichenlaub-Ritter U. Meiosis-activating sterol protects oocytes from precocious chromosome segregation . Hum. Reprod. 2003. 18, N 9. P. 1908-1917. CrossRef PubMed
  16. Dekel N., Piontkewitz Y. Induction of maturation of rat oocytes by interruption of communication in the cumulusoocyte complex . Bull Assoc. Anat. (Nancy). 1991. 75, N 228. P. 51-54.
  18. Dekel N. Cellular, biochemical and molecular mechanisms regulating oocyte maturation . Mol. Cell Endocrinol. 2005. 234, N 1-2. P. 19-25. CrossRef PubMed
  20. Downs S.M., Chen J. EGF-like peptides mediate FSH-induced maturation of cumulus cell-enclosed mouse oocytes . Mol. Reprod. Dev. 2008. 75, N 1. P. 105-114. CrossRef PubMed
  22. Downs S.M., Hunzicker-Dunn M. Differential regulation of oocyte maturation and cumulus expansion in the mouse oocyte-cumulus cell complex by site-selective analogs of cyclic adenosine monophosphate . Dev. Biol. 1995. 172, N 1. P. 72-85. CrossRef PubMed
  24. Ecay T.W., Powers R.D. Differential effects of testosterone and dibutyryl cyclic AMP on the meiotic maturation of mouse oocytes in vitro . J. Exp. Zool. 1990. 253, N 1. P. 88-98. CrossRef PubMed
  26. Farin C.E., Rodriguez K.F., Alexander J.E., Hockney J.E., Herrick J.R., Kennedy-Stoskopf S. The role of transcription in EGF- and FSH-mediated oocyte maturation in vitro . Anim. Reprod. Sci. 2007. N 98. P. 97-112. CrossRef PubMed PubMedCentral
  28. Freudzon L., Norris R.P., Hand A.R., Tanaka S., Saeki Y., Jones T.L., Rasenick M.M., Berlot C.H., Mehlmann L.M., Jaffe L.A. Regulation of meiotic prophase arrest in mouse oocytes by GPR3, a constitutive activator of the Gs G protein . J. Cell Biol. 2005. 171, N 2. P. 255-265. CrossRef PubMed PubMedCentral
  30. Gill A., Jamnongjit M., Hammes S.R. Androgens promote maturation and signaling in mouse oocytes independent of transcription: a release of inhibition model for mammalian oocyte meiosis . Mol. Endocrinol. 2004. 18, N 1. P. 97-104. CrossRef PubMed
  32. Hanafy K.A, Krumenacker J.S, Murad F. NO, nitrotyrosine, and cyclic GMP in signal transduction . Med. Sci. Monit. 2001. 7, N 4. P. 801-819.
  34. Hatano E., Brenner D.A. Akt protects mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis through NK-kappa B activation . Amer. J. Physiol. Gastrointest. Liver Physiol. 2001. 281, N 6. P. 1357-1368. CrossRef PubMed
  36. Hegele-Hartung C., Grützner M., Lessl M., Grondahl C., Ottesen J., Brännström M. Activation of meiotic maturation in rat oocytes after treatment with follicular fluid meiosis-activating sterol in vitro and ex vivo . Biol. Reprod. 2001. 64, N 2. P. 418-424. CrossRef PubMed
  38. Hoshino Y., Yokoo M., Yoshida N., Sasada H., Matsumoto H., Sato E. Phosphatidylinositol 3-kinase and Akt participate in the FSH-induced meiotic maturation of mouse oocytes . Mol. Reprod. Dev. 2004. 69, N 1. P. 77-86. CrossRef PubMed
  40. Hu Y., Cortvrindt R., Smitz J. Effects of aromatase inhibition on in vitro follicle and oocyte development analyzed by early preantral mouse follicle culture . Ibid. 2002.  61, N 4. P. 549-559. CrossRef PubMed
  42. Hubbard C.J. Ovarian cAMP and cGMP fluctuations in the hamster during the oestrous cycle . J. Reprod. Fertil. 1980. 59, N 2. P. 351-355. CrossRef PubMed
  44. Jamnongjit M., Gill A., Hammes S.R. Epidermal growth factor receptor signaling is required for normal ovarian steroidogenesis and oocyte maturation . Proc. Natl. Acad. Sci. USA. 2005. 102, N 45. P. 16257-16262. CrossRef PubMed PubMedCentral
  46. Jin S., Zhang M., Lei L., Wang C., Fu M., Ning G., Xia G. Meiosis activating sterol (MAS) regulate FSH-induced meiotic resumption of cumulus cell-enclosed porcine oocytes via PKC pathway . Mol. Cell Endocrinol. 2006. 249, N 1-2. P. 64-70. CrossRef PubMed
  48. Kalinowski R.R., Berlot C.H., Jones T.L., Ross L.F., Jaffe L.A., Mehlmann L.M. Maintenance of meiotic prophase arrest in vertebrate oocytes by a Gs protein-mediated pathway . Dev. Biol. 2004. 267, N 1. P. 1-13. CrossRef PubMed
  50. Kimura M., Haisa M., Uetsuka H. Takaoka M., Ohkawa T., Kawashima R., Yamatsuji T., Gunduz M., Kaneda Y., Tanaka N., Naomoto Y. TNF combined with IFN-a accelerates NF-kB mediated apoptosis through enhancement of Fas expression in colon cancer cells . Cell Death Differ. 2003. 10, N 6. P. 718-728. CrossRef PubMed
  52. Kurylovicz A., Nauman J. The role of nuclear factor kB in the development of autoimmune diseases: a link between genes and environment . Acta. Biochem. Polonica. 2008. 55, N 4. P. 629-647.
  54. LaPolt P.S., Leung K., Ishimaru R., Tafoya M.A., Youhsin Chen J. Roles of cyclic GMP in modulating ovarian functions . Reprod. Biomed. Online. 2003. 6, N 1. P. 15-23. CrossRef  
  55. Li M., Ai J.S., Xu B.Z., Xiong B., Yin S., Lin S.L., Hou Y., Chen D.Y., Schatten H., Sun Q.Y. Testosterone potentially triggers meiotic resumption by activation of intra-oocyte SRC and MAPK in porcine oocytes . Biol. Reprod. 2008. 79, N 5. P. 897-905. CrossRef PubMed
  57. Li M., Liang C.G., Xiong B., Xu B.Z., Lin S.L., Hou Y., Chen D.Y., Schatten H., Sun Q.Y. PI3-kinase and mitogenactivated protein kinase in cumulus cells mediate EGFinduced meiotic resumption of porcine oocyte . Domest. Anim. Endocrinol. 2008. 34, N 4. P. 360-371. CrossRef PubMed
  59. Li M.,Yu Y.,Yan J.,Yan L.Y., Zhao Y., Li R., Liu P., Hsueh A.J., Qiao J.The role of cilostazol, a phosphodiesterase 3 inhibitor, on oocyte maturation and subsequent pregnancy in mice . PLoS One. 2012. 7, N 1. e.30649. CrossRef PubMed PubMedCentral
  61. Liang C.G., Huo L.J., Zhong Z.S., Chen D.Y., Schatten H., Sun Q.Y. Cyclic adenosine 3',5'-monophosphate-dependent activation of mitogen-activated protein kinase in cumulus cells is essential for germinal vesicle breakdown of porcine cumulus-enclosed oocytes . Endocrinology. 2005. 146, N 10. P. 4437-4444. CrossRef PubMed
  63. Marín Bivens C.L., Grondahl C., Murray A., Blume T., Su Y.Q., Eppig J.J. Meiosis-activating sterol promotes the metaphase I to metaphase II transition and preimplantation developmental competence of mouse oocytes maturing in vitro . Biol. Reprod. 2004. 70, N 5. P. 1458-1464. CrossRef PubMed
  65. Mehlmann L.M. Stops and starts in mammalian oocytes: recent advances in understanding the regulation of meiotic arrest and oocyte maturation . Reproduction. 2005. 130, N 6. P. 791-799. CrossRef PubMed
  67. Motola S., Cao X., Ashkenazi H., Popliker M., Tsafriri A. GnRH actions on rat preovulatory follicles are mediated by paracrine EGF-like factors . Mol. Reprod. Dev. 2006. 73, N 10. P. 1271-1276. CrossRef PubMed
  69. Nakamura Y., Yamagata Y., Sugino N., Takayama H., Kato H. Nitric oxide inhibits oocyte meiotic maturation . Biol. Reprod. 2002. 67, N 5. P. 1588-1592. CrossRef PubMed
  71. Newhall K.J., Criniti A.R., Cheah C.S., Smith K.C., Kafer K.E., Burkart A.D., McKnight G.S. Dynamic anchoring of PKA is essential during oocyte maturation . Curr. Biol. 2006. 16, N 3. P. 321-327. CrossRef PubMed PubMedCentral
  73. Ning G., Ouyang H., Wang S., Chen X., Xu B., Yang J., Zhang H., Zhang M., Xia G. 3',5'-cyclic adenosine monophosphate response element binding protein upregulated cytochrome P450 lanosterol 14alpha-demethylase expression involved in follicle-stimulating hormoneinduced mouse oocyte maturation . Mol. Endocrinol. 2008. 22, N 7. P. 1682-1694. CrossRef PubMed PubMedCentral
  75. Noubani A., Farookhi R., Gutkowska J. B-type natriuretic peptide receptor expression and activity are hormonally regulated in rat ovarian cells . Endocrinology. 2000. 141, N 2. P. 551-559. CrossRef PubMed
  77. Paciolla M. Nuclear factor-kappa-B-inhibitor alpha (NFKBIA) is a developmental marker of NF-κB. p65 activation during in vitro oocyte maturation and early embryogenesis . Hum. Reprod. 2011. 26, N 5. P. 1191-1201. CrossRef PubMed
  79. Park J.Y., Su Y.Q., Ariga M., Law E., Jin S.L., Conti M. EGF-like growth factors as mediators of LH action in the ovulatory follicle . Science. 2004. 303, N 5658. P. 682-684. CrossRef PubMed
  81. Rodriguez K.F., Petters R.M., Crosier A.E., Farin C.E. Roles of gene transcription and PKA subtype activation in maturation of murine oocytes . Reproduction. 2002. 123, N 6. P. 799-806. CrossRef PubMed
  83. Sekiguchi T., Mizutani T., Yamada K., Yazawa T., Kawata H., Yoshino M., Kajitani T., Kameda T., Minegishi T., Miyamoto K. Transcriptional regulation of the epiregulin gene in the rat ovary . Endocrinology. 2002. 143, N 12. P. 4718-4729. CrossRef PubMed
  85. Sela-Abramovich S., Chorev E., Galiani D., Dekel N. Mitogen-activated protein kinase mediates luteinizing hormone-induced breakdown of communication and oocyte maturation in rat ovarian follicles . Ibid. 2005. 146, N 3. P. 1236-1244. CrossRef PubMed
  87. Senthilkumaran B. Recent advances in meiotic maturation and ovulation: comparing mammals and pisces . Front. Biosci. 2011. N 16. P. 1898-1914. CrossRef PubMed
  89. Shimada M., Hernandez-Gonzalez I., Gonzalez-Robayna I., Richards J.S. Paracrine and autocrine regulation of epidermal growth factor-like factors in cumulus oocyte complexes and granulosa cells: key roles for prostaglandin synthase 2 and progesterone receptor . Mol. Endocrinol. 2006. 20, N 6. P. 1352-1365. CrossRef PubMed
  91. Shimada M, Ito J, Yamashita Y, Okazaki T, Isobe N Phos- phatidylinositol 3-kinase in cumulus cells is responsible for both suppression of spontaneous maturation and induction of gonadotropin-stimulated maturation of porcine oocytes . J. Endocrinol. 2003. 179, N 1. P. 25-34. CrossRef PubMed
  93. Shimada M., Terada T. Phosphatidylinositol 3-kinase in cumulus cells and oocytes is responsible for activation of oocyte mitogen-activated protein kinase during meiotic progression beyond the meiosis I stage in pigs . Biol. Reprod. 2001. 64, N 4. P. 1106-1114. CrossRef PubMed
  95. Shimada M, Terada T. FSH and LH induce progesterone production and progesterone receptor synthesis in cumulus cells: a requirement for meiotic resumption in porcine oocytes . Mol. Hum. Reprod. 2002. 8, N 7. P. 612-618. CrossRef PubMed
  97. Shimada M., Zeng W.X., Terada T. Inhibition of phosphatidylinositol 3-kinase or mitogen-activated protein kinase kinase leads to suppression of p34(cdc2) kinase activity and meiotic progression beyond the meiosis I stage in porcine oocytes surrounded with cumulus cells . Biol. Reprod. 2001 65, N 2. P. 442-448. CrossRef PubMed
  99. Siqueira L.C., Barreta M.H., Gasperin B., Bohrer R., Santos J.T., Junior J.B., Oliveira J.F., Gonsalves P.B. Angiotensin II, progesterone, and prostaglandins are sequential steps in the pathway to bovine oocyte nuclear maturation . Theriogenology. 2012. 77, N 9. P. 1779-1787. CrossRef PubMed
  101. Steegers E.A., Hollanders J.M., Jongsma H.W., Hein P.R. Atrial natriuretic peptide and progesterone in ovarian follicular fluid . Gynecol. Obstet. Invest. 1990. 29, N 3. P. 185-187. CrossRef PubMed
  103. Su Y.Q., Denegre J.M., Wigglesworth K., Pendola F.L., O'Brien M.J., Eppig J.J. Oocyte-dependent activation of mitogen-activated protein kinase (ERK1. 2) in cumulus cells is required for the maturation of the mouse oocytecumulus cell complex . Dev. Biol. 2003. 263, N 1. P. 126-138. CrossRef  
  104. Su Y.Q., Wigglesworth K., Pendola F.L., O'Brien M.J., Eppig J.J. Mitogen-activated protein kinase activity in cumulus cells is essential for gonadotropin-induced oocyte meiotic resumption and cumulus expansion in the mouse . Endocrinology. 2002. 143, N 6. P. 2221-2232. CrossRef PubMed
  106. Tao J.Y., Fu Z., Zhang M.L., Xia G., Lei L., Wu Z.L. Nitric oxide influences the meiotic maturation of porcine oocytes cultured in hypoxanthine-supplemented medium . J. Anim. Physiol. Anim. Nutr. (Berl.). 2005. 89, N 1-2. P. 38-44. CrossRef PubMed
  108. Tsafriri A., Cao X., Vaknin K.M., Popliker M. Is meiosis activating sterol (MAS) an obligatory mediator of meiotic resumption in mammals . Mol. Cell Endocrinol. 2002. 187, N 1-2. P. 197-204. CrossRef  
  109. Vigil D., Blumenthal D.K., Brown S., Taylor S.S., Trewhella J. Differential effects of substrate on type I and type II PKA holoenzyme dissociation . Biochemistry. 2004. 43, N 19. P. 5629-5636. CrossRef PubMed
  111. Wang S., Ning G., Chen X., Yang J., Ouyang H., Zhang H., Tai P., Mu X., Zhou B., Zhang M., Xia G. PDE5 modulates oocyte spontaneous maturation via cGMP-cAMP but not cGMP-PKG signalling . Front. Biosci. 2008. N 13. P. 7087-7095. CrossRef PubMed
  113. Webb R.J., Marshall F., Swann K., Carroll J. Folliclestimulating hormone induces a gap junction-dependent dynamic change in [cAMP] and protein kinase a in mammalian oocytes . Dev. Biol. 2002. 246, N 2. P. 441-454. CrossRef PubMed
  115. Xie H., Xia G., Byskov A.G., Andersen C.Y., Bo S., Tao Y. Roles of gonadotropins and meiosis-activating sterols in meiotic resumption of cultured follicle-enclosed mouse oocytes . Mol. Cell Endocrinol. 2004. 218, N 1-2. P. 155-163. CrossRef PubMed
  117. Yamagata Y., Nakamura Y., Sugino N., Harada A., Takayama H., Kashida S., Kato H. Alterations in nitrate. nitrite and nitric oxide synthase in preovulatory follicles in gonadotropin-primed immature rat . Endocrinol. J. 2002. 49, N 2. P. 219-226. CrossRef PubMed
  119. Yamashita Y., Nishibori M., Terada T., Isobe N., Shimada M. Gonadotropin-induced delta14-reductase and delta7- reductase gene expression in cumulus cells during meiotic resumption of porcine oocytes . Endocrinology. 2005. 146, N 1. P. 186-194. CrossRef PubMed
  121. Zhang M., Ouyang H., Xia G. The signal pathway of gonadotrophins-induced mammalian oocyte meiotic resumption . Mol. Hum. Reprod. 2009. 15, N 7. P. 399-409. CrossRef PubMed
  123. Zhang M., Tao Y., Xia G., Xie H., Hong H., Wang F., Lei L. Atrial natriuretic peptide negatively regulates folliclestimulating hormone-induced porcine oocyte maturation and cumulus expansion via cGMP-dependent protein kinase pathway . Theriogenology. 2005. 64, N 4. P. 902-916. CrossRef PubMed
  125. Zhang M., Tao Y., Zhou B., Xie H., Wang F., Lei L., Huo L., Sun Q., Xia G. Atrial natriuretic peptide inhibits the actions of FSH and forskolin in meiotic maturation of pig oocytes via different signalling pathways . J. Mol. Endocrinol. 2005. 34, N 2. P. 459-72. CrossRef PubMed
  127. Zhang M., Xia G., Zhou B., Wang C. Gonadotropincontrolled mammal oocyte meiotic resumption . Front. Biosci. 2007. N 12. P. 282-296.   CrossRef PubMed
  129. Zhang X., Armstrong D.T. Effects of follicle-stimulating hormone and ovarian steroids during in vitro meiotic maturation on fertilization of rat oocytes.Gamete Res. 1989; 23(3):267-77. CrossRef PubMed

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