Molecular mechanisms of oogenesis

 This literature review is devoted to the molecular mechanisms of oogenesis and depletion of the ovarian reserve. One of the factors in this process is constantly changing environment of the ovaries, both during intrauterine development and the postnatal period. Numerous mechanisms and factors  affecting the internal environment of the female gonad are described, such as stem cell factor (SCF), which regulates migration of primordial germ cells and survival of early oocytes, insulin-like growth factor I (IGF-I), and leukocyte migration inhibitory factor (LMIF). The capabilities of the endocrine system, namely sex steroids, which can both replenish the number of germ cells and deplete the ovarian reserve through the expression of apoptotic markers, were shown. Apoptosis causes degeneration of most of the germ cells formed during oogenesis. The molecular mechanisms and factors involved in this process are numerous.
Pathways mediated by mitochondria of germ cells and external pathways mediated by receptors of the cell surface were described. A mediator between two apoptotic pathways was established – the Bid protein (BH3-interacting domain death agonist), the activation of which triggers the apoptosis mechanism of the intrafollicular microenvironment. Some other factors were identified that mediate programmed germ cell death and result in diminished ovarian reserve: eukaryotic elongation factor 2 kinase (eEF-2 K), PUMA and NOXA genes, the absence of growth factors and members of tumor necrosis factor (TNF) family. Changes in the epigenetic modification of chromatin in the follicular and germ cells, oxidative stress, decreased DNA repair, and the involvement of the genes BRAC1, RAD51, ERCC2, and H2AX associated with this process can also affect reproductive health and the ovarian reserve. A significant role of mitochondrial dysfunction of follicular cells in depletion of the ovarian reserve is of great interest, which leads to impaired oocyte competence, deteriorates the gamete quality, and depletes  the ovarian reserve. Therefore, oogenesis depends on a huge number of factors and the internal environment of the ovaries, the knowledge of which  can maintain the stability of the reproductive function and preserve the quality of the ovarian reserve.  

1. Денисенко М.В., Курцер М.А., Курило Л.Ф. Динамика формирования фолликулярного резерва яичников. Андрология и генитальная хирургия. 2016; 17: 20–28. DOI: 10.17650/2070-9781-2016-17-2-20-28.

2. Зенкина В.Г. Формирование фолликулярного резерва яичников. Бюллетень сибирской медицины. 2018; 17 (3): 197–206. DOI: 10.20538/1682-0363-2018-3-197–206.

3. Зенкина В.Г., Солодкова О.А. Молекулярно- генетические механизмы организации и развития яичника. Бюллетень сибирской медицины. 2018; 17 (2): 133–142. DOI: 10.20538/1682-0363-2018-2-133–142.

4. Турдыбекова Я.Г. Фолликулогенез и фолликулярный запас яичника в норме и патологии: аспекты (этапы) клинико-морфологического изучения. Вестник КазНМУ. 2019; 1: 41–45.

5. Hsueh A.J.W., Kawamura K., Cheng Y., Fauser B.C.J.M. Intraovarian control of early folliculogenesis. Endocr. Rev. 2015; 36 (1): 1–24. DOI: 10.1210/er.2014-1020.

6. Sato E., Kimura N., Yokoo M., Miyake Y., Ikeda J.E. Morphodynamics of ovarian follicles during oogenesis in mice. Microsc. Res. and Techn. 2006; 69 (6): 427–435. DOI: 10.1002/jemt.20302.

7. Pan B., Li J. The art of oocyte meiotic arrest regulation. Reprod. Biol. Endocrinol. 2019; 17 (1): 8. DOI: 10.1186/s12958-018-0445-8.

8. Fulton N., Martins da Silva S.J., Bayne R.A.L., Anderson R.A. Germ cell proliferation and apoptosis in the developing human ovary. J. Clin. Endocrinol. Metab. 2005; 90: 4664–4670.

9. Moniruzaman M., Sakamaki K., Akazawa Y., Miyano T. Oocyte growth and follicular development in KIT-deficient Fas-knockout mice. Reproduction. 2007; 133: 117–125. DOI: 10.1530/REP-06-0161.

10. Hansen K.R., Hodnett G.M., Knowlton N., Craig LB. Correlation of ovarian reserve tests with histologically determined primordial follicle number. Fertil Steril. 2011; 95: 170–175 DOI: 10.1016/j.fertnstert.2010.04.006.

11. Thuwanut P., Comizzoli P., Wildt D.E., Keefer C.L., Songsasen N. Stem cell factor promotes in vitro ovarian follicle development in the domestic cat by upregulating c-kit mRNA expression and stimulating the phosphatidylinositol 3-kinase/AKT pathway. Reprod. Fertil. Dev. 2017; 29 (7): 1356–1368. DOI: 10.1071/RD16071.

12. Nilsson E., Detzel C., Skinner M. Platelet-derived growth factor modulates the primordial to primary follicle transition. Reproduction. 2006; 6: 1007–1015. DOI: 10.1530/rep.1.00978.

13. Greenfeld C.R., Roby K.F., Pepling M.E., Babus J.K., Terranova P.F., Flaws J.A. Tumor necrosis factor (TNF) receptor type 2 is an important mediator of TNF alpha function in the mouse ovary. Biol. Reprod. 2007; 76: 224–231. DOI: 10.1095/biolreprod.106.055509.

14. Monget P., Bobe J., Gougeon A., Fabre S., Monniaux D., Dalbies-Tran R. The ovarian reserve in mammals: a functional and evolutionary perspective. Mol. Cell Endocrinol. 2012; 356 (1-2): 2–12. DOI: 10.1016/j.mce.2011.07.046.

15. Rimon-Dahari N., Yerushalmi-Heinemann L., Alyagor L., Dekel N. Ovarian folliculogenesis. Results Probl. Cell Differ. 2016; 58: 167–190. DOI: 10.1007/978-3-319-31973-5_7.

16. Wear H.M., McPike M.J., Watanabe K.H. From primordial germ cells to primordial follicles: a review and visual representation of early ovarian development in mice. J. Ovarian Res. 2016; 9: 36. DOI: 10.1186/s13048-016-0246-7.

17. Dutta S., Mark-Kappeler C.J., Hoyer P.B., Pepling M.E. The steroid hormone environment during primordial follicle formation in perinatal mouse ovaries. Biol. Reprod. 2014; 91 (3): 68. DOI: 10.1095/biolreprod.114.119214.

18. Ghafari F., Gutierrez C.G., Hartshorne G.M. Apoptosis in mouse fetal and neonatal oocytes during meiotic prophase one. BMC Dev. Biol. 2007; 7: 87. DOI: 10.1186/1471-213X-7-87.

19. Wu X., Fu Y., Sun X., Liu C., Chai M., Chen C., Dai L., Gao Y., Jiang H., Zhang J. The possible FAT1-mediated apoptotic pathways in porcine cumulus cells. Cell Biol. Int. 2017; 41 (1): 24–32. DOI: 10.1002/cbin.10695.

20. Childs A.J., Kinnell H.L., He J., Anderson R.A. LIN28 is selectively expressed by primordial and pre-meiotic germ cells in the human fetal ovary. Stem Cells Dev. 2012; 21 (13): 2343–2349. DOI: 10.1089/scd.2011.0730.

21. Hartshorne G.M., Lyrakou S., Hamoda H., Oloto E., Ghafari F. Oogenesis and cell death in human prenatal ovaries: what are the criteria for oocyte selection? Mol. Hum. Reprod. 2009; 15 (12): 805–819. DOI: 10.1093/molehr/gap055.

22. DeFelici M., Lobascio A.M., Klinger F.G. Cell death in fetal oocytes: many players for multiple pathways. Autophagy. 2008; 4: 240–242. DOI: 10.4161/auto.5410.

23. Gkountela S., Li Z., Vincent J.J., Zhang K.X., Chen A., Pellegrini M., Clark A.T. The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nat. Cell Biol. 2013; 15 (1): 113–122. DOI: 10.1038/ncb2638.

24. Fabbri R., Zamboni C., Vicenti R., Macciocca M., Paradisi R., Seracchioli R. Update on oogenesis in vitro. Minerva Ginecol. 2018; 70 (5): 588–608. DOI: 10.23736/S0026-4784.18.04273-9.

25. Зенкина В.Г., Каредина В.С., Солодкова О.А., Слуцкая Т.Н., Юферева А.Л. Морфология яичников андрогенизированных крыс на фоне приема экстракта из кукумарии. Тихоокеанский медицинский журнал. 2007; 4: 70–72.

26. Banerjee S., Banerjee S., Saraswat G., Bandyopadhyay S.A., Kabir S.N. Female reproductive aging is master-planned at the level of ovary. PLoS One. 2014; 9 (5): e96210. DOI: 10.1371/journal.pone.0096210.

27. Зенкина В.Г. Факторы ангиогенеза при развитии физиологических и патологических процессов женской гонады. Бюллетень сибирской медицины. 2016; 15 (4): 111–119. DOI: 10.20538/1682-0363-2016-4-111–119.

28. Tiwari M., Prasad S., Tripathi A., Pandey A.N., Ali I., Singh A.K., Shrivastav T.G., Chaube S.K. Apoptosis in mammalian oocytes: a review. Apoptosis. 2015; 20 (8): 1019–1025. DOI: 10.1007/s10495-015-1136-y.

29. Gartner A., Boag P.R., Blackwell T.K. Germline survival and apoptosis. WormBook. 2008; 4: 1–20. DOI: 10.1895/wormbook.1.145.1.

30. Klinger F.G., Rossi V., De Felici M. Multifaceted programmed cell death in the mammalian fetal ovary. Int. J. Dev. Biol. 2015; 59 (1-3): 51–54. DOI: 10.1387/ijdb.150063fk.

31. Linkermann A., Green D.R. Necroptosis. N. Engl. J. Med. 2014; 370 (5): 455–465. DOI: 10.1056/NEJMra1310050.

32. Rodrigues P., Limback D., McGinnis L.K., Plancha C.E., Albertini D.F. Multiple mechanisms of germ cell loss in the perinatal mouse ovary. Reproduction. 2009; 137: 709–720. DOI: 10.1530/REP-08-0203.

33. Gawriluk T.R., Hale A.N., Flaws J.A., Dillon C.P., Green D.R., Rucker E.B. Ankophagy is a cell survival program for female germ cells in the murine ovary. Reproduction. 2011; 141 (6): 759–765. DOI: 10.1530/REP-10-0489.

34. Kimura T., Kaga Y., Sekita Y., Fujikawa K., Nakatani T., Odamoto M., Funaki S., Ikawa M., Abe K., Nakano T. Pluripotent stem cells derived from mouse primordial germ cells by small molecule compounds. Stem Cells. 2015; 33 (1): 45–55. DOI: 10.1002/stem.1838.

35. Tingen C., Kim A., Woodruff T.K. The primordial pool of follicles and nest breakdown in mammalian ovaries. Mol. Hum. Reprod. 2009; 15 (12): 795–803. DOI: 10.1093/molehr/gap073.

36. Lin J., Chen F., Sun M.J., Zhu J., Li Y.W., Pan L.Z., Zhang J., Tan J.H. The relationship between apoptosis, chromatin configuration, histone modification and competence of oocytes: A study using the mouse ovary-holding stress model. Sci. Rep. 2016; 6: 28347. DOI: 10.1038/srep28347.

37. Seidler E.A., Moley K.H. Metabolic determinants of mitochondrial function in oocytes. Semin. Reprod. Med. 2015; 33 (6): 396–400. DOI: 10.1055/s-0035-1567822.

38. Boucret L., Chao de la Barca J.M., Morinière C., Desquiret V., Ferré-L’Hôtellier V., Descamps P., Marcaillou C, Reynier P., Procaccio V., May-Panloup P. Relationship between diminished ovarian reserve and mitochondrial biogenesis in cumulus cells. Hum. Reprod. 2015; 30 (7): 1653–1664. DOI: 10.1093/humrep/dev114.

39. Wang C., Zhou B., Xia G. Mechanisms controlling germline cyst breakdown and primordial follicle formation. Cell Mol. Life Sci. 2017; 74 (14): 2547–2566. DOI: 10.1007/s00018-017-2480-6.

40. Zhang J.Q., Gao B.W., Wang J., Ren Q.L., Chen J.F., Ma Q., Zhang Z.J., Xing B.S. Critical role of foxo1 in granulosa cell apoptosis caused by oxidative stress and protective effects of grape seed procyanidin B2. Oxid. Med. Cell Longev. 2016; 2016: 6147345. DOI: 10.1155/2016/6147345.

41. Chu H.P., Liao Y., Novak J.S., Hu Z., Merkin J.J., Shymkiv Y., Braeckman B.P., Dorovkov M.V., Nguyen A., Clifford P.M., Nagele R.G., Harrison D.E., Ellis R.E., Ryazanov A.G. Germline quality control: eFK2K stands guard to eliminate defective oocytes. Dev. Cell. 2014; 28: 561–572. DOI: 10.1016/j.devcel.2014.01.027.

42. Hutt K.J. The role of BH3-only proteins in apoptosis within the ovary. Reproduction. 2015; 149 (2): R81–R89. DOI: 10.1530/REP-14-0422.

43. Myers M., Morgan F.H., Liew S.H., Zerafa N., Gamage T.U., Sarraj M., Cook M., Kapic I., Sutherland A., Scott C.L., Strasser A., Findlay J.K., Kerr J.B., Hutt K.J. PUMA regulates germ cell loss and primordial follicle endowment in mice. Reproduction. 2014; 148 (2): 211–219. DOI: 10.1530/REP-13-0666.

44. Omari S., Waters M., Naranian T., Kim K., Perumalsamy A.L., Chi M., Greenblatt E., Moley K.H., Opferman J.T., Jurisicova A. Mcl-1 is a key regulator of the ovarian reserve. Cell Death Dis. 2015; 6 (5): e1755. DOI: 10.1038/cddis.2015.95.

45. Kerr J.B., Hutt K.J., Michalak E.M., Cook M., Vandenberg C.J., Liew S.H., Bouillet P., Mills A., Scott C.L., Findlay J.K., Strasser A. et al. DNA damage-induced primordial follicle oocyte apoptosis and loss of fertility require Tap63-mediated maturation of Puma and Noxa. Mol. Cell. 2012; 48 (3): 343–352. DOI: 10.1016/j.molcel.2012.08.017.

46. Sui X.X., Luo L.L., Xu J.J., Fu Y.C. Evidence that FOXO3 is involved in oocyte apoptosis in the neonatal rat ovary. Biochem Cell Biol. 2010; 88 (4): 621–628. DOI: 10.1139/O10-001.

47. Cui L.L., Yang G., Pan J., Zhang C. Tumor necrosis factor alpha knockout increases fertility of mice. Theriogenology. 2011; 75 (5): 867–876. DOI: 10.1016/j.theriogenology.2010.10.029.

48. Jung D., Kee K. insights into female germ cell biology: from in vivo development to in vitro derivations. Asian J. Androl. 2015; 17 (3): 415–420. DOI: 10.4103/1008-682X.148077.

49. Govindaraj V., Rao A.J. Comparative proteomic analysis of primordial follicles from ovaries of immature and aged rats. Syst. Biol. Reprod. Med. 2015; 61 (6): 367–375. DOI: 10.3109/19396368.

50. May-Panloup P., Boucret L., Chao de la Barca J.M., Desquiret-Dumas V., Ferré-L’Hotellier V., Morinière C., Descamps P., Procaccio V., Reynier P. Ovarian ageing: the role of mitochondria in oocytes and follicles. Hum. Reprod. Update. 2016; 22 (6): 725–743. DOI: 10.1093/humupd/dmw028.