TOR Serine-Threonine Kinases; Multiprotein Complexes; Mechanistic Target of Rapamycin Complex 1; Transcription Factors; RNA, Small Interfering; Gonadotropin-Releasing Hormone; Female; Animals; Mice; Humans; TOR Serine-Threonine Kinases/metabolism; Multiprotein Complexes/genetics; Multiprotein Complexes/metabolism; Mechanistic Target of Rapamycin Complex 1/metabolism; Transcription Factors/metabolism; Hypothalamus/metabolism; Gonadotropin-Releasing Hormone/metabolism; Mammals/genetics; Ovarian Cysts; Raptors/genetics; Raptors/metabolism; cysts; fertility; folliculogenesis; hypothalamus; neurons; ovary; raptor; Mammals; Raptors; Medicine (all)
Abstract :
[en] [en] CONTEXT: Mammalian target of rapamycin complex 1 (mTORC1) is an essential sensor that regulates fundamental biological processes like cell growth, proliferation and energy metabolism. The treatment of disease by sirolimus, a mTORC1 inhibitor, causes adverse effects, such as female fertility disorders.
AIMS: The objective of the study was to decipher the reproductive consequences of a downregulation of mTORC1 in the hypothalamus.
METHODS: The reduced expression of mTORC1 was induced after intracerebroventricular injection of lentivirus expressing a short hairpin RNA (shRNA) against regulatory associated protein of TOR (raptor) in adult female mice (ShRaptor mice).
KEY RESULTS: The ShRaptor mice were fertile and exhibited a 15% increase in the litter size compared with control mice. The histological analysis showed an increase in antral, preovulatory follicles and ovarian cysts. In the hypothalamus, the GnRH mRNA and FSH levels in ShRaptor mice were significantly elevated.
CONCLUSIONS: These results support the hypothesis that mTORC1 in the central nervous system participates in the regulation of female fertility and ovarian function by influencing the GnRH neuronal activity.
IMPLICATIONS: These results suggest that a lower mTORC1 activity directly the central nervous system leads to a deregulation in the oestrous cycle and an induction of ovarian cyst development.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Tartarin, Pauline; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
Keller, Matthieu; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
Guibert, Edith; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
Trives, Elliott ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie de la différenciation sexuelle du cerveau ; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
Bourdon, Guillaume; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
Chamero, Pablo; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
Negre, Didier; Université de Lyon, IFR 128, INSERM-U758, Ecole Normale Supérieure de Lyon, Lyon F-69007, France
Cornilleau, Fabien; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
Guillory, Vanaique; INRA ISP, Université François Rabelais de Tours, UMR 1282, Nouzilly, France
JeanPierre, Eric; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
Costa, Caroline; Université de Lyon, IFR 128, INSERM-U758, Ecole Normale Supérieure de Lyon, Lyon F-69007, France
Migrenne, Stéphanie; University Paris Diderot-Paris 7-Unit of Functional and Adaptive Biology (BFA) EAC 7059 CNRS, Paris, France
Dupont, Joelle; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
Froment, Pascal ; CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly F-37380, France
This work was supported by the national program \u2018FERTiNERGY\u2019, funded by the French National Research Agency (ANR). Pauline Tartarin was supported by a French fellowship from the \u2018Minist\u00E8re de l\u2019\u00E9ducation et de la recherche\u2019. Acknowledgements
Alam H, Maizels ET, Park Y, Ghaey S, Feiger ZJ, Chandel NS, Hunzicker-Dunn M (2004) Follicle-stimulating hormone activation of hypoxia-inducible factor-1 by the phosphatidylinositol 3-kinase/AKT/Ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) pathway is necessary for induction of select protein markers of follicular differentiation. Journal of Biological Chemistry 279, 19431 19440. doi:10.1074/jbc.M401235200
Alfadhli E, Koh A, Albaker W, Bhargava R, Ackerman T, McDonald C, Ryan EA, Shapiro AMJ, Senior PA (2009) High prevalence of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus after clinical islet transplantation. Transplant International 22, 622 625. doi:10.1111/j.1432-2277.2009.00839.x
Bachmann F, Glander P, Budde K, Bachmann C (2018) High incidence of ovarian cysts in women receiving mTOR inhibitors after renal transplantation. Journal of Women s Health 27, 394 398. doi:10.1089/ jwh.2017.6451
Bererhi L, Flamant M, Martinez F, Karras A, Thervet E, Legendre C (2003) Rapamycin-induced oligospermia. Transplantation 76, 885 886. doi:10.1097/01.TP.0000079830.03841.9E
Bertoldo MJ, Guibert E, Faure M, Guillou F, Ramé C, Nadal-Desbarats L, Foretz M, Viollet B, Dupont J, Froment P (2016) Specific deletion of AMP-Activated protein kinase (α1AMPK) in mouse Sertoli cells modifies germ cell quality. Molecular and Cellular Endocrinology 423, 96 112. doi:10.1016/j.mce.2016.01.001
Braun M, Young J, Reiner CS, Poster D, Krauer F, Kistler AD, Kristanto P, Wang X, Liu Y, Loffing J, Andreisek G, von Eckardstein A, Senn O, Wöthrich RP, Serra AL (2012a) Low-dose oral sirolimus and the risk of menstrual-cycle disturbances and ovarian cysts: Analysis of the randomized controlled SUISSE ADPKD trial. PLoS ONE 7, e45868. doi:10.1371/journal.pone.0045868
Braun M, Young J, Reiner CS, Poster D, Wöthrich RP, Serra AL (2012b) Ovarian toxicity from sirolimus. New England Journal of Medicine 366, 1062 1064. doi:10.1056/NEJMc1113145
Brus M, Meurisse M, Franceschini I, Keller M, Lévy F (2010) Evidence for cell proliferation in the sheep brain and its down-regulation by parturition and interactions with the young. Hormones and Behavior 58, 737 746. doi:10.1016/j.yhbeh.2010.07.006
Chang RJ (2007) The reproductive phenotype in polycystic ovary syndrome. Nature Clinical Practice Endocrinology & Metabolism 3, 688 695. doi:10.1038/ncpendmet0637
Cota D, Matter EK, Woods SC, Seeley RJ (2008) The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. Journal of Neuroscience 28, 7202 7208. doi:10.1523/ JNEUROSCI.1389-08.2008
Coyral-Castel S, Tosca L, Ferreira G, Jeanpierre E, Rame C, Lomet D, Caraty A, Monget P, Chabrolle C, Dupont J (2008) The effect of AMP-Activated kinase activation on gonadotrophin-releasing hormone secretion in GT1-7 cells and its potential role in hypothalamic regulation of the oestrous cyclicity in rats. Journal of Neuroendocrinology 20, 335 346. doi:10.1111/j.1365-2826.2007.01643.x
Cure P, Pileggi A, Froud T, Norris PM, Baidal DA, Cornejo A, Hafiz MM, Ponte G, Poggioli R, Yu J, Saab A, Selvaggi G, Ricordi C, Alejandro R (2004) Alterations of the female reproductive system in recipients of islet grafts. Transplantation 78, 1576 1581. doi:10.1097/01.TP. 0000147301.41864.C0
Framarino-dei-Malatesta M, Derme M, Manzia TM, Iaria G, De Luca L, Fazzolari L, Napoli A, Berloco P, Patel T, Orlando G, Tisone G (2013) Impact of mTOR-I on fertility and pregnancy: state of the art and review of the literature. Expert Review of Clinical Immunology 9, 781 789. doi:10.1586/1744666X.2013.824243
Froment P, Seurin D, Hembert S, Levine JE, Pisselet C, Monniaux D, Binoux M, Monget P (2002) Reproductive abnormalities in human IGF binding protein-1 transgenic female mice. Endocrinology 143, 1801 1808 doi:10.1210/endo.143.5.8815
Froment P, Staub C, Hembert S, Pisselet C, Magistrini M, Delaleu B, Seurin D, Levine JE, Johnson L, Binoux M, Monget P (2004) Reproductive abnormalities in human insulin-like growth factor-binding protein-1 transgenic male mice. Endocrinology 145, 2080 2091. doi:10.1210/ en.2003-0956
González A, Hall MN (2017) Nutrient sensing and TOR signaling in yeast and mammals. The EMBO Journal 36, 397 408. doi:10.15252/embj. 201696010
Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Molecular Cell 30, 214 226. doi:10.1016/j.molcel.2008.03.003
Heitman J, Movva NR, Hall MN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905 909. doi:10.1126/science.1715094
Hu F, Xu Y, Liu F (2016) Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis. American Journal of Physiology-Endocrinology and Metabolism 310, E994 E1002. doi:10.1152/ajpendo.00121.2016
Huyghe E, Zairi A, Nohra J, Kamar N, Plante P, Rostaing L (2007) Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: An overview. Transplant International 20, 305 311. doi:10.1111/j.1432-2277.2006.00423.x
Kayampilly PP, Menon KMJ (2007) Follicle-stimulating hormone increases tuberin phosphorylation andmammalian target of rapamycin signaling through an extracellular signal-regulated kinase-dependent pathway in rat granulosa cells. Endocrinology 148,3950 3957. doi:10.1210/ en.2007-0202
Kogasaka Y, Hoshino Y, Hiradate Y, Tanemura K, Sato E (2013) Distribution and association of mTOR with its cofactors, raptor and rictor, in cumulus cells and oocytes during meiotic maturation in mice. Molecular Reproduction and Development 80, 334 348. doi:10.1002/mrd.22166
Mabuchi S, Altomare DA, Connolly DC, Klein-Szanto A, Litwin S, Hoelzle MK, Hensley HH, Hamilton TC, Testa JR (2007) RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Research 67, 2408 2413. doi:10.1158/00085472.CAN-06-4490
McLaughlin M, Patrizio P, Kayisli U, Luk J, Thomson TC, Anderson RA, Telfer EE, Johnson J (2011) mTOR kinase inhibition results in oocyte loss characterized by empty follicles in human ovarian cortical strips cultured in vitro. Fertility and Sterility 96, 1154 1159.e1. doi:10.1016/j.fertnstert.2011.08.040
Morrison CD, Xi X, White CL, Ye J, Martin RJ (2007) Amino acids inhibit Agrp gene expression via an mTOR-dependent mechanism. American Journal of Physiology-Endocrinology and Metabolism 293, E165 E171. doi:10.1152/ajpendo.00675.2006
Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, Kiyama H, Yonezawa K, Yamanaka S (2004) mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Molecular and Cellular Biology 24, 6710 6718. doi:10.1128/ MCB.24.15.6710-6718.2004
Nègre D, Mangeot P-E, Duisit G, Blanchard S, Vidalain P-O, Leissner P, Winter A-J, Rabourdin-Combe C, Mehtali M, Moullier P, Darlix J-L, Cosset F-L (2000) Characterization of novel safe lentiviral vectors derived from simian immunodeficiency virus (SIVmac251) that efficiently transduce mature human dendritic cells. Gene Therapy 7, 1613 1623. doi:10.1038/sj.gt.3301292
Palaniappan M, Menon KMJ (2010) Human chorionic gonadotropin stimulates theca-interstitial cell proliferation and cell cycle regulatory proteins by a cAMP-dependent activation of AKT/mTORC1 signaling pathway. Molecular Endocrinology 24, 1782 1793. doi:10.1210/ me.2010-0044
Pierre P, Froment P, Nègre D, Ramé C, Barateau V, Chabrolle C, Lecomte P, Dupont J (2009) Role of adiponectin receptors, AdipoR1 and AdipoR2, in the steroidogenesis of the human granulosa tumor cell line, KGN. Human Reproduction 24, 2890 2901. doi:10.1093/ humrep/dep292
Prevot V, Bellefontaine N, Baroncini M, Sharif A, Hanchate NK, Parkash J, Campagne C, De Seranno S (2010) Gonadotrophin-releasing hormone nerve terminals, tanycytes and neurohaemal junction remodelling in the adult median eminence: functional consequences for reproduction and dynamic role of vascular endothelial cells. Journal of Neuroendocrinology 22, 639 649. doi:10.1111/j.1365-2826.2010. 02033.x
Roa J, Garcia-Galiano D, Varela L, Sánchez-Garrido MA, Pineda R, Castellano JM, Ruiz-Pino F, Romero M, Aguilar E, Ĺopez M, Gaytan F, Diéguez C, Pinilla L, Tena-Sempere M (2009) The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology 150, 5016 5026. doi:10.1210/en.2009-0096
Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH (1994) RAFT1: A mammalian protein that binds to FKBP12 in a rapamycindependent fashion and is homologous to yeast TORs. Cell 78,35 43. doi:10.1016/0092-8674(94)90570-3
Shivaswamy V, Ochsner L, Maroni D, Wang C, Passer J, Clure CE, Hamel FG, Davis JS, Larsen J (2011) Tacrolimus and sirolimus induce reproductive abnormalities in female rats. Transplantation 91, 1333 1339. doi:10.1097/TP.0b013e31821c1e8b
Skrzypek J, Krause W (2007) Azoospermia in a renal transplant recipient during sirolimus (rapamycin) treatment. Andrologia 39, 198 199. doi:10.1111/j.1439-0272.2007.00787.x
Solon CS, Franci D, Ignacio-Souza LM, Romanatto T, Roman EA, Arruda AP, Morari J, Torsoni AS, Carneiro EM, Velloso LA (2012) Taurine enhances the anorexigenic effects of insulin in the hypothalamus of rats. Amino Acids 42, 2403 2410. doi:10.1007/s00726-011-1045-5
Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. Journal of Biological Chemistry 284, 8023 8032. doi:10.1074/jbc.M900301200
Wolfson RL, Sabatini DM (2017) The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metabolism 26, 301 309. doi:10.1016/j.cmet.2017.07.001
Xu Y, Parmar A, Roux E, Balbis A, Dumas V, Chevalier S, Posner BI (2012) Epidermal growth factor-induced vacuolar (H+)-ATPase assembly: A role in signaling via mTORC1 activation. Journal of Biological Chemistry 287, 26409 26422. doi:10.1074/jbc.M112.352229
Yu J, Yaba A, Kasiman C, Thomson T, Johnson J (2011) mTOR controls ovarian follicle growth by regulating granulosa cell proliferation. PLoS ONE 6, e21415. doi:10.1371/journal.pone.0021415
Zuber J, Anglicheau D, Elie C, Bererhi L, TimsitM-O,Mamzer-Bruneel M-F, Ciroldi M, Martinez F, Snanoudj R, Hiesse C, Kreis H, Eustache F, Laborde K, Thervet E, Legendre C (2008) Sirolimusmay reduce fertility in male renal transplant recipients. American Journal of Transplantation 8, 1471 1479. doi:10.1111/j.1600-6143.2008.02267.x
