Subfertility with Defective Folliculogenesis in Female Mice Lacking Testicular Orphan Nuclear Receptor 4

The Endocrine Society - Tập 22 Số 4 - Trang 858-867 - 2008
Lu-Min Chen1,2, Ruey-Sheng Wang2,3, Yi-Fen Lee2, Ning-Chun Liu2, Yu‐Jia Chang2,3, Cheng‐Chia Wu2, Shaozhen Xie2, Yao‐Ching Hung1, Chawnshang Chang2
1Department of Obstetrics and Gynecology (L.-M.C., Y.-C.H.), China Medical University Hospital, Taichung 404, Taiwan
2George Whipple Laboratory for Cancer Research (L.-M.C., R.-S.W., Y.-F.L., N.-C.L., Y.-J.C., C.-C.W., S.X., C.C.), Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14620
3Taipei Medical University and Hospital (R.-S.W., Y.-J.C.), Taipei 110, Taiwan

Tóm tắt

Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in male mice. However, its roles in female fertility and ovarian function remain largely unknown. Here we found female mice lacking TR4 (TR4−/−) displayed subfertility and irregular estrous cycles. TR4−/− female mice ovaries were smaller with fewer or no preovulatory follicles and corpora lutea. After superovulation, TR4−/− female mice produced fewer oocytes, preovulatory follicles, and corpora lutea. In addition, more intensive granulosa apoptosis was found in TR4−/− ovaries. Functional analyses suggest that subfertility in TR4−/− female mice can be due to an ovarian defect with impaired folliculogenesis rather than a deficiency in pituitary gonadotropins. Molecular mechanism dissection of defective folliculogenesis found TR4 might induce LH receptor (LHR) gene expression via direct binding to its 5′ promoter. The consequence of reduced LHR expression in TR4−/− female mice might then result in reduced gonadal sex hormones via reduced expression of enzymes involved in steroidogenesis. Together, our results showed TR4 might play essential roles in normal folliculogenesis by influencing LHR signals. Modulation of TR4 expression and/or activation via its upstream signals or unidentified ligand(s) might allow us to develop small molecule(s) to control folliculogenesis.

Từ khóa


Tài liệu tham khảo

Schmidt, 1995, Infertility and the seeking of infertility treatment in a representative population., Br J Obstet Gynaecol, 102, 978, 10.1111/j.1471-0528.1995.tb10905.x

Murphy, 2000, Models of luteinization., Biol Reprod, 63, 2, 10.1095/biolreprod63.1.2

Chang, 1994, Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily., Proc Natl Acad Sci USA, 91, 6040, 10.1073/pnas.91.13.6040

Hirose, 1994, TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily., Mol Endocrinol, 8, 1667

Lee, 2002, Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily., J Steroid Biochem Mol Biol, 81, 291, 10.1016/S0960-0760(02)00118-8

Lee, 1999, Convergence of two repressors through heterodimer formation of androgen receptor and testicular orphan receptor-4: a unique signaling pathway in the steroid receptor superfamily., Proc Natl Acad Sci USA, 96, 14724, 10.1073/pnas.96.26.14724

Lee, 1998, Negative feedback control of the retinoid-retinoic acid/retinoid X receptor pathway by the human TR4 orphan receptor, a member of the steroid receptor superfamily., J Biol Chem, 273, 13437, 10.1074/jbc.273.22.13437

Lee, 1999, Differential regulation of direct repeat 3 vitamin D3 and direct repeat 4 thyroid hormone signaling pathways by the human TR4 orphan receptor., J Biol Chem, 274, 16198, 10.1074/jbc.274.23.16198

Shyr, 2002, Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells., J Biol Chem, 277, 14622, 10.1074/jbc.M110051200

Zhang, 2000, Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor., J Biol Chem, 275, 2763, 10.1074/jbc.275.4.2763

Mu, 2004, Targeted inactivation of testicular nuclear orphan receptor 4 delays and disrupts late meiotic prophase and subsequent meiotic divisions of spermatogenesis., Mol Cell Biol, 24, 5887, 10.1128/MCB.24.13.5887-5899.2004

El-Hefnawy, 1996, Regulation of function of the murine luteinizing hormone receptor promoter by cis- and trans-acting elements in mouse Leydig tumor cells., Mol Cell Endocrinol, 119, 207, 10.1016/0303-7207(96)03815-4

Huhtaniemi, 1992, The murine luteinizing hormone and follicle-stimulating hormone receptor genes: transcription initiation sites, putative promoter sequences and promoter activity., Mol Cell Endocrinol, 88, 55, 10.1016/0303-7207(92)90009-U

Collins, 2004, Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4., Proc Natl Acad Sci USA, 101, 15058, 10.1073/pnas.0405700101

Indrapichate, 1992, Biological actions of monoclonal luteinizing hormone/human chorionic gonadotropin receptor antibodies., Biol Reprod, 46, 265, 10.1095/biolreprod46.2.265

Ascoli, 2002, The lutropin/choriogonadotropin receptor, a 2002 perspective., Endocr Rev, 23, 141, 10.1210/edrv.23.2.0462

Zhang, 2001, Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice., Mol Endocrinol, 15, 172, 10.1210/mend.15.1.0582

Pakarainen, 2005, Knockout of luteinizing hormone receptor abolishes the effects of follicle-stimulating hormone on preovulatory maturation and ovulation of mouse Graafian follicles., Mol Endocrinol, 19, 2591, 10.1210/me.2005-0075

Moore, 2004, Are BMP-15 and GDF-9 primary determinants of ovulation quota in mammals?, Trends Endocrinol Metab, 15, 356, 10.1016/j.tem.2004.08.008

Latronico, 1996, Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene., N Engl J Med, 334, 507, 10.1056/NEJM199602223340805

Huhtaniemi, 2005, Mutations in human gonadotropin and gonadotropin-receptor genes., Endocrine, 26, 207, 10.1385/ENDO:26:3:207

Latronico, 1998, A homozygous microdeletion in helix 7 of the luteinizing hormone receptor associated with familial testicular and ovarian resistance is due to both decreased cell surface expression and impaired effector activation by the cell surface receptor., Mol Endocrinol, 12, 442, 10.1210/mend.12.3.0077

Billig, 1993, Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis., Endocrinology, 133, 2204, 10.1210/endo.133.5.8404672

Peluso, 1999, Progesterone maintains large rat granulosa cell viability indirectly by stimulating small granulosa cells to synthesize basic fibroblast growth factor., Biol Reprod, 60, 290, 10.1095/biolreprod60.2.290

Blaschuk, 1989, Estradiol stimulates cadherin expression in rat granulosa cells., Dev Biol, 136, 564, 10.1016/0012-1606(89)90283-2

Kim, 2007, TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression., Biochem Biophys Res Commun, 361, 323, 10.1016/j.bbrc.2007.06.168

Ferraretti, 2000, Female poor responders., Mol Cell Endocrinol, 161, 59, 10.1016/S0303-7207(99)00225-7

Cheng, 2002, A role for the androgen receptor in follicular atresia of estrogen receptor β knockout mouse ovary., Biol Reprod, 66, 77, 10.1095/biolreprod66.1.77

Mather, 1980, Establishment and characterization of two distinct mouse testicular epithelial cell lines., Biol Reprod, 23, 243, 10.1095/biolreprod23.1.243

Heinlein, 1999, Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor γ., J Biol Chem, 274, 16147, 10.1074/jbc.274.23.16147

Thông tin
Thông tin xuất bản

The Endocrine Society

Tập 22 Số 4

858-867

Thông tin tác giả