Transcriptional Profiling of Luteinizing Hormone Receptor-deficient Mice Before and After Testosterone Treatment Provides Insight into the Hormonal Control of Postnatal Testicular Development and Leydig Cell Differentiation

Overview

Journal Biol Reprod

Publisher Oxford University Press

Specialty Reproductive Medicine

Date 2010 Feb 19

PMID 20164437

Citations 11

Authors

D K Griffin

P J Ellis

B Dunmore

J Bauer

M H Abel

N A Affara

Affiliations

Soon will be listed here.

Abstract

Luteinizing hormone (LH) is a key regulator of male fertility through its effects on testosterone secretion by Leydig cells. Transcriptional control of this is, however, currently poorly understood. Mice in which the LH receptor is knocked out (LuRKO) show reduced testicular size, reduced testosterone, elevated serum LH, and a spermatogenic arrest that can be rescued by the administration of testosterone. Using genome-wide transcription profiling of LuRKO and control testes during postnatal development and following testosterone treatment, we show that the transcriptional effects of LH insensitivity are biphasic, with an early testosterone-independent phase and a subsequent testosterone-dependent phase. Testosterone rescue re-enables the second, testosterone-dependent phase of the normal prepubertal transcription program and permits the continuation of spermatogenesis. Examination of the earliest responses to testosterone highlights six genes that respond rapidly in a dose-dependent fashion to the androgen and that are therefore candidate regulatory genes associated with the testosterone-driven progression of spermatogenesis. In addition, our transcriptional data suggest a model for the replacement of fetal-type Leydig cells by adult-type cells during testicular development in which a testosterone feedback switch is necessary for adult Leydig cell production. LH signaling affects the timing of the switch but is not a strict requirement for Leydig cell differentiation.

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References

De Gendt K, Atanassova N, Tan K, de Franca L, Parreira G, McKinnell C . Development and function of the adult generation of Leydig cells in mice with Sertoli cell-selective or total ablation of the androgen receptor. Endocrinology. 2005; 146(9):4117-26. DOI: 10.1210/en.2005-0300. View

Bhardwaj A, Rao M, Kaur R, Buttigieg M, Wilkinson M . GATA factors and androgen receptor collaborate to transcriptionally activate the Rhox5 homeobox gene in Sertoli cells. Mol Cell Biol. 2008; 28(7):2138-53. PMC: 2268436. DOI: 10.1128/MCB.01170-07. View

Mikkila T, Toppari J, Paranko J . Effects of neonatal exposure to 4-tert-octylphenol, diethylstilbestrol, and flutamide on steroidogenesis in infantile rat testis. Toxicol Sci. 2006; 91(2):456-66. DOI: 10.1093/toxsci/kfj156. View

Maratou K, Forster T, Costa Y, Taggart M, Speed R, Ireland J . Expression profiling of the developing testis in wild-type and Dazl knockout mice. Mol Reprod Dev. 2003; 67(1):26-54. DOI: 10.1002/mrd.20010. View

Khatri P, Sellamuthu S, Malhotra P, Amin K, Done A, Draghici S . Recent additions and improvements to the Onto-Tools. Nucleic Acids Res. 2005; 33(Web Server issue):W762-5. PMC: 1160233. DOI: 10.1093/nar/gki472. View

Zhang F, Pakarainen T, Poutanen M, Toppari J, Huhtaniemi I . The low gonadotropin-independent constitutive production of testicular testosterone is sufficient to maintain spermatogenesis. Proc Natl Acad Sci U S A. 2003; 100(23):13692-7. PMC: 263875. DOI: 10.1073/pnas.2232815100. View

OShaughnessy P, Morris I, Huhtaniemi I, Baker P, Abel M . Role of androgen and gonadotrophins in the development and function of the Sertoli cells and Leydig cells: data from mutant and genetically modified mice. Mol Cell Endocrinol. 2008; 306(1-2):2-8. DOI: 10.1016/j.mce.2008.11.005. View

Tsai M, Yeh S, Wang R, Yeh S, Zhang C, Lin H . Differential effects of spermatogenesis and fertility in mice lacking androgen receptor in individual testis cells. Proc Natl Acad Sci U S A. 2006; 103(50):18975-80. PMC: 1748162. DOI: 10.1073/pnas.0608565103. View

Spaliviero J, Jimenez M, Allan C, Handelsman D . Luteinizing hormone receptor-mediated effects on initiation of spermatogenesis in gonadotropin-deficient (hpg) mice are replicated by testosterone. Biol Reprod. 2003; 70(1):32-8. DOI: 10.1095/biolreprod.103.019398. View

10.

Fox M, Ares V, Turek P, Haqq C, Pera R . Feasibility of global gene expression analysis in testicular biopsies from infertile men. Mol Reprod Dev. 2003; 66(4):403-21. DOI: 10.1002/mrd.10364. View

11.

Willems A, De Gendt K, Allemeersch J, Smith L, Welsh M, Swinnen J . Early effects of Sertoli cell-selective androgen receptor ablation on testicular gene expression. Int J Androl. 2009; 33(3):507-17. DOI: 10.1111/j.1365-2605.2009.00964.x. View

12.

OShaughnessy P, Baker P, Sohnius U, Haavisto A, Charlton H, Huhtaniemi I . Fetal development of Leydig cell activity in the mouse is independent of pituitary gonadotroph function. Endocrinology. 1998; 139(3):1141-6. DOI: 10.1210/endo.139.3.5788. View

13.

Guo R, Yu Z, Guan J, Ge Y, Ma J, Li S . Stage-specific and tissue-specific expression characteristics of differentially expressed genes during mouse spermatogenesis. Mol Reprod Dev. 2004; 67(3):264-72. DOI: 10.1002/mrd.20026. View

14.

De Gendt K, Swinnen J, Saunders P, Schoonjans L, Dewerchin M, Devos A . A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci U S A. 2004; 101(5):1327-32. PMC: 337052. DOI: 10.1073/pnas.0308114100. View

15.

Denolet E, De Gendt K, Allemeersch J, Engelen K, Marchal K, Van Hummelen P . The effect of a sertoli cell-selective knockout of the androgen receptor on testicular gene expression in prepubertal mice. Mol Endocrinol. 2005; 20(2):321-34. DOI: 10.1210/me.2005-0113. View

16.

Hardy M, Kelce W, Klinefelter G, EWING L . Differentiation of Leydig cell precursors in vitro: a role for androgen. Endocrinology. 1990; 127(1):488-90. DOI: 10.1210/endo-127-1-488. View

17.

Pakarainen T, Zhang F, Makela S, Poutanen M, Huhtaniemi I . Testosterone replacement therapy induces spermatogenesis and partially restores fertility in luteinizing hormone receptor knockout mice. Endocrinology. 2004; 146(2):596-606. DOI: 10.1210/en.2004-0913. View

18.

Ye X . Lysophospholipid signaling in the function and pathology of the reproductive system. Hum Reprod Update. 2008; 14(5):519-36. DOI: 10.1093/humupd/dmn023. View

19.

Rath N, Wang Z, Lu M, Morrisey E . LMCD1/Dyxin is a novel transcriptional cofactor that restricts GATA6 function by inhibiting DNA binding. Mol Cell Biol. 2005; 25(20):8864-73. PMC: 1265795. DOI: 10.1128/MCB.25.20.8864-8873.2005. View

20.

Eacker S, Shima J, Connolly C, Sharma M, Holdcraft R, Griswold M . Transcriptional profiling of androgen receptor (AR) mutants suggests instructive and permissive roles of AR signaling in germ cell development. Mol Endocrinol. 2007; 21(4):895-907. DOI: 10.1210/me.2006-0113. View