Journal of Endocrinology and Reproduction

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Membrane Estrogen Receptor 1 is Required for Normal Reproduction in Male and Female Mice


Affiliations
1 Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, United States
2 Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
     

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Steroid hormones, acting through their cognate nuclear receptors, are critical for many reproductive and non-reproductive functions. Over the past two decades, it has become increasingly clear that in addition to cytoplasmic/nuclear steroid receptors that alter gene transcription when liganded, a small fraction of cellular steroid receptors are localized to the cell membranes, where they mediate rapid steroid hormone effects. 17β-Estradiol (E2), a key steroid hormone for both male and female reproduction, acts predominately through its main receptor, estrogen receptor 1 (ESR1). Most ESR1 is nuclear; however, 5-10 % of ESR1 is localized to the cell membrane after being palmitoylated at cysteine 451 in mice. This review discusses reproductive phenotypes of a newly-developed mouse model with a C451A point mutation that precludes membrane targeting of ESR1. This transgenic mouse, termed the nuclear-only ESR1 (NOER) mouse, shows extensive male and female reproductive abnormalities and infertility despite normally functional nuclear ESR1 (nESR1). These results provide the first in vivo evidence that membrane-initiated E2/ESR1 signaling is required for normal male and female reproductive functions and fertility. Signaling mechanisms for membrane ESR1 (mESR1), as well as how mESR1 works with nESR1 to mediate estrogen effects, are still being established. We discuss some possible mechanisms by which mESR1 might facilitate nESR1 signaling, as well as the emerging evidence that mESR1 might be a major mediator of epigenetic effects of estrogens, which are potentially linked to various adult-onset pathologies.

Keywords

Efferent Ductules, 17β-Estradiol, Spermatogenesis, Testis, Uterus.
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  • Thornton JW. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc Natl Acad Sci U S A. 2001; 98: 5671–6. https://doi.org/10.1073/pnas.091553298 PMid:11331759 PMCid:PMC33271

  • Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR. Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science. 1990; 249: 1266–72. https://doi.org/10.1126/science.2119054 PMid:2119054

  • Weikum ER, Knuesel MT, Ortlund EA, Yamamoto KR. Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol. 2017; 18: 159–74. https://doi.org/10.1038/nrm.2016.152 PMid:28053348

  • Mitre–Aguilar IB, Cabrera–Quintero AJ, Zentella–Dehesa A. Genomic and non–genomic effects of glucocorticoids: implications for breast cancer. Int J Clin Exp Pathol. 2015; 8: 1–10. PMid:25755688 PMCid:PMC4348864

  • Levin ER, Hammes SR. Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol. 2016; 17: 783–97. https://doi.org/10.1038/ nrm.2016.122 PMid:27729652 PMCid:PMC5649368

  • Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. Estrogens in male physiology. Physiol Rev. 2017; 97: 995–1043. https://doi.org/10.1152/physrev.00018.2016 PMid:28539434

  • Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev. 2003; 83: 965–1016. https://doi.org/10.1152/physrev.00003.2003 PMid:12843413

  • Wehling M. Rapid actions of aldosterone revisited: Receptors in the limelight. J Steroid Biochem Mol Biol. 2017: 176:94–8 https://doi.org/10.1016/j.jsbmb.2017.01.016 PMid:28126566

  • Klinge CM. Estrogens regulate life and death in mitochondria. J Bioenerg Biomembr. 2017; 49:307–24. https://doi.org/10.1007/s10863–017–9704–1 PMid:28401437

  • Selye H. Correlations between the chemical structure and the pharmacological actions of the steroids. Endocrinology. 1942; 30: 437–53. https://doi.org/10.1210/endo–30–3–437

  • Spach C, Streeten DH. Retardation of sodium exchange in dog erythrocytes by physiological concentrations of aldosterone, in vitro. J Clin Invest. 1964; 43 21727. https://doi.org/10.1172/JCI104906 PMid:14162530 PMCid:PMC289515

  • Pietras RJ, Szego CM. Endometrial cell calcium and estrogen action. Nature. 1975; 253: 357–59. https://doi. org/10.1038/253357a0

  • Levin ER. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol. 2005; 19 1951–9. https://doi.org/10.1210/me.2004–0390 PMid:15705661 PMCid:PMC1249516

  • Wang C, Liu Y, Cao JM. G protein–coupled receptors: extranuclear mediators for the non–genomic actions of steroids. Int J Mol Sci. 2014; 15: 15412–25. https://doi.org/10.3390/ijms150915412 PMid:25257522 PMCid:PMC4200746

  • Falkenstein E, Norman AW, Wehling M. Mannheim classification of nongenomically initiated (rapid) steroid action(s). J Clin Endocrinol Metab. 2000; 85: 2072–5. https://doi.org/10.1210/jcem.85.5.6516 PMid:10843198

  • Blackmore PF, Beebe SJ, Danforth DR, Alexander N. Progesterone and 17 alpha–hydroxyprogesterone. Novel stimulators of calcium influx in human sperm. J Biol Chem. 1990; 265: 1376–80. PMid:2104840

  • Razandi M, Pedram A, Greene GL, Levin ER. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ER–alpha and ER–beta expressed in Chinese hamster ovary cells. Mol Endocrinol. 1999; 13: 307–19. https://doi.org/10.1210/mend.13.2.0239 https://doi.org/10.1210/me.13.2.307 PMid:9973260

  • Pedram A, Razandi M, Levin ER. Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol. 2006; 20: 1996–2009. https://doi.org/10.1210/me.2005–0525 PMid:16645038

  • Clouse SD. Brassinosteroid signal transduction: from receptor kinase activation to transcriptional networks regulating plant development. Plant Cell. 2011, 23: 1219–30. https://doi.org/10.1105/tpc.111.084475 PMid:21505068 PMCid:PMC3101532

  • Madak–Erdogan Z, Kim SH, Gong P, et al. Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues.Sci Signal. 2016; 9 ra53. https://doi.org/10.1126/scisignal.aad8170 PMid:27221711 PMCid:PMC4896643

  • Sen A, De Castro I, Defranco DB, et al. Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation. J Clin Invest. 2012; 122: 2469–81. https://doi.org/10.1172/JCI62044 PMid:22684108 PMCid:PMC3386821

  • Daniel AR, Gaviglio AL, Knutson TP, et al. Progesterone receptor–B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1– and estrogen receptorcontaining transcription complexes. Oncogene. 2015, 34: 506–15. https://doi.org/10.1038/onc.2013.579 PMid:24469035 PMCid:PMC4112172

  • Migliaccio A, Castoria G, Di Domenico M, et al. Steroid–induced androgen receptor–oestradiol receptor beta–Src complex triggers prostate cancer cell proliferation, EMBO J. 2000; 19: 5406–17. https://doi.org/10.1093/emboj/19.20.5406 PMid:11032808 PMCid:PMC314017

  • Jia G, Aroor AR, Sowers JR. Estrogen and mitochondria function in cardiorenal metabolic syndrome, Prog Mol Biol Transl Sci. 2014; 127: 229–49. https://doi.org/10.1016/B978–0–12–394625–6.00009–X PMid:25149220 PMCid:PMC4318630

  • Mattingly KA, Ivanova MM, Riggs KA, Wickramasinghe NS, Barch MJ, Klinge CM. Estradiol stimulates transcription of nuclear respiratory factor–1 and increases mitochondrial biogenesis. Mol Endocrinol. 2008; 22: 60922. https://doi.org/10.1210/me.2007–0029 PMid:18048642 PMCid:PMC2262171

  • Ivanova MM, Radde BN, Son J, et al.. Estradiol and tamoxifen regulate NRF–1 and mitochondrial function in mouse mammary gland and uterus. J Mol Endocrinol. 2013; 51: 233–46. https://doi.org/10.1530/JME–13–0051 PMid:23892277 PMCid:PMC3772954

  • Ivanova MM, Luken KH, Zimmer AS, et al. Tamoxifen increases nuclear respiratory factor 1 transcription by activating estrogen receptor beta and AP–1 recruitment to adjacent promoter binding sites. FASEB J. 2011; 25: 140216. https://doi.org/10.1096/fj.10–169029 PMid:21233487 PMCid:PMC3058701

  • Ribas V, Drew BG, Zhou Z, et al. Skeletal muscle action of estrogen receptor alpha is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci Transl Med. 2016; 8: 334ra354. https:// doi.org/10.1126/scitranslmed.aad3815 PMid:27075628 PMCid:PMC4934679

  • Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptoralpha knockout mice. Proc Natl Acad Sci U S A. 2000; 97 12729–34. https://doi.org/10.1073/pnas.97.23.12729 PMid:11070086 PMCid:PMC18832

  • Altmann T. Recent advances in brassinosteroid molecular genetics. Curr Opin Plant Biol. 1998; 1: 378–83. https://doi.org/10.1016/S1369–5266(98)80259–8

  • Li L, Haynes MP, Bender JR. Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Proc Natl Acad Sci U S A. 2003; 100: 4807–12. https://doi.org/10.1073/pnas.0831079100 PMid:12682286 PMCid:PMC153637

  • Flouriot G, Griffin C, Kenealy M, Sonntag–Buck V, Gannon F. Differentially expressed messenger RNA isoforms of the human estrogen receptor–alpha gene are generated by alternative splicing and promoter usage. Mol Endocrinol. 1998; 12: 1939–54. https://doi.org/10.1210/mend.12.12.0209 https://doi.org/10.1210/me.12.12.1939 PMid:9849967

  • Wang Z, Zhang X, Shen P, et al. A variant of estrogen receptor–{ alpha}, hER–{alpha}36: transduction of estrogen– and antiestrogen–dependent membrane–initiated mitogenic signaling. Proc Natl Acad Sci U S A. 2006; 103: 9063–8. https://doi.org/10.1073/pnas.0603339103 PMid:16754886 PMCid:PMC1482566

  • Pedram A, Razandi M, Sainson RC, Kim JK Hughes CC, Levin ERA. conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem. 2007; 282: 22278–88. https://doi.org/10.1074/jbc.M611877200 PMid:17535799

  • Razandi M, Pedram A, Levin ER. Heat shock protein 27 is required for sex steroid receptor trafficking to and functioning at the plasma membrane. Mol Cell Biol. 2010; 30: 3249–61. https://doi.org/10.1128/MCB.01354–09 PMid:20439495 PMCid:PMC2897588

  • Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER. ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol Endocrinol. 2002; 16: 100–15. https://doi.org/10.1210/mend.16.1.0757 PMid:11773442

  • Razandi M, Pedram A, Park ST, Levin ER. Proximal events in signaling by plasma membrane estrogen receptors. J Biol Chem. 2003; 278: 2701–12. https://doi.org/10.1074/jbc. M205692200 PMid:12421825

  • Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ. The role of Shc and insulin–like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane. Proc Natl Acad Sci U S A. 2004; 101: 2076–81. https://doi.org/10.1073/pnas.0308334100 PMid:14764897 PMCid: PMC357054

  • Bredfeldt TG, Greathouse KL, Safe SH, Hung MC, Bedford MT, Walker CL. Xenoestrogen–induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol Endocrinol. 2010; 24: 993–1006. https://doi.org/10.1210/me.2009–0438 PMid:20351197 PMCid:PMC2870935

  • Pedram A, Razandi M, Lewis M, Hammes S, Levin ER. Membrane–localized estrogen receptor α is required for normal organ development and function. Dev Cell. 2014; 29: 482–490. https://doi.org/10.1016/j.devcel.2014.04.016 PMid:24871949 PMCid: PMC4062189

  • Adlanmerini M, Solinhac R, Abot A, et al. Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue–specific roles for membrane versus nuclear actions. Proc Natl Acad Sci U S A. 2014; 111: E283–90. https://doi.org/10.1073/pnas.1322057111 PMid:24371309 PMCid:PMC3896153

  • Nanjappa MK, Hess, RA, Medrano TI, Locker SH, Levin ER, Cooke PS. Membrane–localized estrogen receptor 1 is required for normal male reproductive development and function in mice, Endocrinology. 2016; 157 2909–19. https://doi.org/10.1210/en.2016–1085 PMid:27145009 PMCid:PMC4929544

  • Hess RA, Bunick D, Lee KH, et al. A role for oestrogens in the male reproductive system. Nature. 1997; 390 509–12. https://doi.org/10.1038/37352 PMid:9393999 PMCid:PMC5719867

  • Joseph A, Hess RA, Schaeffer DJ, et al. Absence of estrogen receptor alpha leads to physiological alterations in the mouse epididymis and consequent defects in sperm function. Biol Reprod. 2010; 82: 948–57. https://doi.org/10.1095/biolreprod. 109.079889 PMid:20130267 PMCid:PMC2857635

  • Joseph A, Shur, B,D, Ko C, Chambon P, Hess RA. Epididymal hypo–osmolality induces abnormal sperm morphology and function in the estrogen receptor alpha knockout mouse. Biol Reprod. 2010; 82: 958–67. https://doi.org/10.1095/biolreprod.109.080366 PMid:20130266 PMCid:PMC2857636

  • Mahato D, Goulding EH, Korach KS, Eddy EM. Spermatogenic cells do not require estrogen receptoralpha for development or function. Endocrinology. 2000; 141: 1273–6. https://doi.org/10.1210/endo.141.3.7439 PMid:10698205

  • Joseph A, Shur BD, Hess RA. Estrogen, efferent ductules, and the epididymis, Biol Reprod. 2011; 84: 207–17. https://doi.org/10.1095/biolreprod.110.087353 PMid:20926801 PMCid:PMC3071263

  • Hess RA. Estrogen in the adult male reproductive tract: a review. Reprod Biol Endocrinol. 2003; 1: 52. https:// doi.org/10.1186/1477–7827–1–52 PMid:12904263 PMCid:PMC179885

  • Hess RA. Disruption of estrogen receptor signaling and similar pathways in the efferent ductules and initial segment of the epididymis. Spermatogenesis. 2014; 4 e979103. https:// doi.org/10.4161/21565562.2014.979103 PMid:26413389 PMCid:PMC4581051

  • Toda K, Okada T, Hayashi Y, Saibara T. Preserved tissue structure of efferent ductules in aromatase–deficient mice. J Endocrinol. 2008; 199: 137–46. https://doi.org/10.1677/JOE–08–0257 PMid:18653624

  • Cho HW, Nie R, Carnes K, Zhou Q, Sharief NA, Hess RA. The antiestrogen ICI 182,780 induces early effects on the adult male mouse reproductive tract and long–term decreased fertility without testicular atrophy. Reprod Biol Endocrinol. 2003; 1 57. https://doi.org/10.1186/1477–78271–57 PMid:12959643 PMCid:PMC194658

  • Zhou Q, Clarke L, Nie R, et al. Estrogen action and male fertility: roles of the sodium/hydrogen exchanger–3 and fluid reabsorption in reproductive tract function. Proc Natl Acad Sci U S A. 2001; 98: 14132–7. https://doi.org/10.1073/pnas.241245898 PMid:11698654 PMCid:PMC61180

  • Cooke PS, Nanjappa MK, Tevosian SG, Hess RA. Roles of membrane and nuclear estrogen receptors in spermatogenesis. In The Biology of Spermatogenesis: Developments and Clinical Implications of Research (Cheng CY. (ed.)). CRC Press, Abingdon, England 2017.

  • Akingbemi BT, Ge R, Rosenfeld CS, et al. Estrogen receptoralpha gene deficiency enhances androgen biosynthesis in the mouse Leydig cell. Endocrinology. 2003; 144: 84–93. https://doi.org/10.1210/en.2002–220292 PMid:12488333

  • Jensen EV, Jordan VC. The estrogen receptor: a model for molecular medicine, Clin Cancer Res. 2003; 9: 1980–9. PMid:12796359

  • Hewitt SC, Harrell JC, Korach KS. Lessons in estrogen biology from knockout and transgenic animals Annu Rev Physiol. 2005: 67; 285–308. https://doi.org/10.1146/ annurev.physiol.67.040403.115914 PMid:15709960

  • Grody WW, Schrader WT, O’Malley BW. Activation, transformation, and subunit structure of steroid hormone receptors. Endocr Rev. 1982; 3: 141–63. https://doi.org/10.1210/edrv–32–141 PMid:7044769

  • Szego CM, Davis JS. Adenosine 3’,5’–monophosphate in rat uterus: acute elevation by estrogen. Proc Natl Acad Sci U S A. 1967; 58:1711–18. https://doi.org/10.1073/ pnas.58.4.1711

  • Pietras RJ, Szego CM. Specific binding sites for estrogen at the outer surfaces of isolated endometrial cells. Nature. 1977; 265: 69–72. https://doi.org/10.1038/265069a0

  • Kazi AA, Koos RD. Estrogen–induced activation of hypoxiainducible factor–1alpha, vascular endothelial growth factor expression, and edema in the uterus are mediated by the phosphatidylinositol 3–kinase/Akt pathway. Endocrinology.

  • ; 148: 2363–74. https://doi.org/10.1210/en.2006–1394 PMid:17272396

  • Ali S, Metzger D, Bornert JM, Chambon P. Modulation of transcriptional activation by ligand–dependent phosphorylation of the human oestrogen receptor A/B region. EMBO J. 1993; 12: 1153–60. PMid:8458328 PMCid:PMC413317

  • Joel PB, Traish AM, Lannigan DA. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Mol Endocrinol. 1995; 9: 1041–52. https://doi.org/10.1210/me.9.8.1041 https://doi.org/10.1210/mend.9.8.7476978 PMid:7476978

  • Kato S, Endoh H, Masuhiro Y, et al. Activation of the estrogen receptor through phosphorylation by mitogen–activated protein kinase. Science. 1995; 270: 1491–94. https://doi.org/10.1126/science.270.5241.1491 PMid:7491495

  • Lopez GN, Turck CW, Schaufele F, Stallcup MR, Kushner PJ. Growth factors signal to steroid receptors through mitogen–activated protein kinase regulation of p160 coactivator activity. J Biol Chem. 2001; 276: 22177–82. https://doi.org/10.1074/jbc.M010718200 PMid:11301320

  • York B, O’Malley BW. Steroid receptor coactivator (SRC) family: masters of systems biology. J Biol Chem. 2010; 285: 38743–50. https://doi.org/10.1074/jbc.R110.193367 PMid:20956538 PMCid:PMC2998129

  • York B, Yu C, Sagen JV, et al. Reprogramming the posttranslational code of SRC–3 confers a switch in mammalian systems biology. Proc Natl Acad Sci U S A. 2010; 107: 11122–7. https://doi.org/10.1073/pnas.1005262107 PMid:20534466 PMCid:PMC2890746

  • La Rosa P, Pesiri V, Leclercq G, Marino M, Acconcia F. Palmitoylation regulates 17beta–estradiol–induced estrogen receptor–alpha degradation and transcriptional activity. Mol Endocrinol. 2012; 26: 762–74. https://doi.org/10.1210/me.2011–1208 PMid:22446104 PMCid:PMC5417099

  • Li S, Washburn KA, Moore R, et al. Developmental exposure to diethylstilbestrol elicits demethylation of estrogenresponsive lactoferrin gene in mouse uterus. Cancer Res. 1997; 57: 4356–9. PMid:9331098

  • Doherty LF, Bromer JG, Zhou Y, Aldad TS, Taylor HS. In utero exposure to diethylstilbestrol (DES) or bisphenol–A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer, Horm Cancer. 2010; 1: 146–55. https://doi.org/10.1007/s12672–010–0015–9 PMid:21761357 PMCid:PMC3140020

  • Bromer JG, Zhou Y, Taylor MB, Doherty L, Taylor HS. Bisphenol–A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. FASEB J. 2010; 24: 2273–80. https://doi.org/10.1096/fj.09–140533 PMid:20181937 PMCid:PMC3230522

  • Cosentino C, Di Domenico M, Porcellini A, et al. p85 regulatory subunit of PI3K mediates cAMP–PKA and estrogens biological effects on growth and survival. Oncogene. 2007; 26: 2095–103. https://doi.org/10.1038/sj.onc.1210027 PMid:17016431

  • Greathouse KL, Bredfeldt T, Everitt JI, et al. Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res. 2012; 10: 546–57. https://doi.org/10.1158/15417786.MCR–11–0605 PMid:22504913 PMCid:PMC3879949

  • Wong RL, Walker CL. Molecular pathways: environmental estrogens activate nongenomic signaling to developmentally reprogram the epigenome. Clin Cancer Res. 2013; 19: 3732–7. https://doi.org/10.1158/1078–0432.CCR–13–0021 PMid:23549878 PMCid:PMC3879948

  • Jiao L, Liu, X. Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2. Science. 2015, 350: aac4383. https://doi.org/10.1126/science.aac4383 PMid:26472914 PMCid:PMC5220110

  • Yoo KH, Hennighausen L. EZH2 methyltransferase and H3K27 methylation in breast cancer. Int J Biol Sci. 2012; 8: 59–65. https://doi.org/10.7150/ijbs.8.59

  • Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002; 419: 624–9. https://doi.org/10.1038/nature01075 PMid:12374981

  • Zingg D, Debbache J, Schaefer SM, et al. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nat Commun. 2015; 6: 6051. https://doi.org/10.1038/ncomms7051 PMid:25609585

  • Wang Q, Trevino LS, Lee Yean Wong R, et al. Reprogramming of the epigenome by MLL1 links early–life environmental exposures to prostate cancer risk. Mol Endocrinol. 2016; me20151310. https://doi.org/10.1210/me.2015–1310

  • Jefferson, WN, Chevalier DM, Phelps JY, et al. Persistently altered epigenetic marks in the mouse uterus after neonatal estrogen exposure. Mol Endocrinol. 2013; 27: 1666–1677. https://doi.org/10.1210/me.2013–1211 PMid:24002655 PMCid:PMC3787132

  • Mishra BP, Ansari, K,I, Mandal SS. Dynamic association of MLL1, H3K4 trimethylation with chromatin and Hox gene expression during the cell cycle. FEBS J. 2009; 276: 1629–0. https://doi.org/10.1111/j.1742–4658.2009.06895.x PMid:19220463

  • Ansari KI, Kasiri S, Hussain , Mandal SS. Mixed lineage leukemia histone methylases play critical roles in estrogenmediated regulation of HOXC13. FEBS J. 2009; 276: 7400–11. https://doi.org/10.1111/j.1742–4658.2009.07453.x PMid:19922474

  • Ansari KI, Hussain I, Shrestha B, Kasiri S, Mandal SS. HOXC6 Is transcriptionally regulated via coordination of MLL histone methylase and estrogen receptor in an estrogen environment. J Mol Biol. 2011; 411: 334–49. https://doi.org/10.1016/j.jmb.2011.05.050 PMid:21683083 PMCid:PMC3143278

  • McEwan IJ. Bakers yeast rises to the challenge: reconstitution of mammalian steroid receptor signalling in S. cerevisiae. Trends Genet. 2001; 17: 239–43. https://doi.org/10.1016/S0168–9525(01)02273–9

  • Wollam J, Antebi A. Sterol regulation of metabolism, homeostasis, and development. Annu Rev Biochem. 2011; 80: 885–916. https://doi.org/10.1146/annurevbiochem081308–165917 PMid:21495846 PMCid: PMC3918218

  • Schlattner U, Vafopoulou X, Steel CG, Hormann RE, Lezzi M. Non–genomic ecdysone effects and the invertebrate nuclear steroid hormone receptor EcR––new role for an “old” receptor? Mol Cell Endocrinol. 200; 247: 64–72. https://doi.org/10.1016/j.mce.2005.12.051

  • Guo H, Li L, Aluru M, Aluru S, Yin Y. Mechanisms and networks for brassinosteroid regulated gene expression. Curr Opin Plant Biol. 2013; 16: 545–53. https://doi.org/10.1016/j.pbi.2013.08.002 PMid:23993372

  • Jaillais Y, Vert G. Brassinosteroid signaling and BRI1 dynamics went underground, Curr Opin Plant Biol. 2016: 33: 92–100. https://doi.org/10.1016/j.pbi.2016.06.014 PMid:27419885 PMCid: PMC5055102

  • Hii CS, Ferrante, A. The non–genomic actions of vitamin D. Nutrients. 2016; 8: 135. https://doi.org/10.3390/nu8030135 PMid:26950144 PMCid:PMC4808864


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  • Membrane Estrogen Receptor 1 is Required for Normal Reproduction in Male and Female Mice

Abstract Views: 345  |  PDF Views: 1

Authors

Manjunatha K. Nanjappa
Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, United States
Ana M. Mesa
Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, United States
Sergei G. Tevosian
Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, United States
Laura de Armas
Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, United States
Rex A. Hess
Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
Indrani C. Bagchi
Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
Paul S. Cooke
Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, United States

Abstract


Steroid hormones, acting through their cognate nuclear receptors, are critical for many reproductive and non-reproductive functions. Over the past two decades, it has become increasingly clear that in addition to cytoplasmic/nuclear steroid receptors that alter gene transcription when liganded, a small fraction of cellular steroid receptors are localized to the cell membranes, where they mediate rapid steroid hormone effects. 17β-Estradiol (E2), a key steroid hormone for both male and female reproduction, acts predominately through its main receptor, estrogen receptor 1 (ESR1). Most ESR1 is nuclear; however, 5-10 % of ESR1 is localized to the cell membrane after being palmitoylated at cysteine 451 in mice. This review discusses reproductive phenotypes of a newly-developed mouse model with a C451A point mutation that precludes membrane targeting of ESR1. This transgenic mouse, termed the nuclear-only ESR1 (NOER) mouse, shows extensive male and female reproductive abnormalities and infertility despite normally functional nuclear ESR1 (nESR1). These results provide the first in vivo evidence that membrane-initiated E2/ESR1 signaling is required for normal male and female reproductive functions and fertility. Signaling mechanisms for membrane ESR1 (mESR1), as well as how mESR1 works with nESR1 to mediate estrogen effects, are still being established. We discuss some possible mechanisms by which mESR1 might facilitate nESR1 signaling, as well as the emerging evidence that mESR1 might be a major mediator of epigenetic effects of estrogens, which are potentially linked to various adult-onset pathologies.

Keywords


Efferent Ductules, 17β-Estradiol, Spermatogenesis, Testis, Uterus.

References





DOI: https://doi.org/10.18311/jer%2F2017%2F21013