This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Apostolakis, E. M. Articles by O’Malley, B. W. Search for Related Content PubMed PubMed Citation Articles by Apostolakis, E. M. Articles by O’Malley, B. W.

Acute Disruption of Select Steroid Receptor Coactivators Prevents Reproductive Behavior in Rats and Unmasks Genetic Adaptation in Knockout Mice

Department of Molecular and Cell Biology, Baylor College of Medicine (E.M.A., B.W.O.), Houston, Texas 77030; Department of Pharmacology, University of Louisville (D.Z.), Louisville, Kentucky 40292; Krieger School of Arts and Sciences, The John Hopkins University (M.R.), Baltimore, Maryland 21218; and Department of Cell Biology and Physiology, University of Pittsburgh (S.O.), Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Dr. Ede Marie Apostolakis, Department of Molecular and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: edea{at}bcm.tmc.edu.

Estrogen (E) and progesterone exert profound influence on development and reproduction. In vitro, steroid receptor coactivators (SRCs) are nuclear proteins that interact with DNA-bound steroid receptors to potentiate their transcriptional efficiency. We examined the effects of antisense oligonucleotides to SRC-1, SRC-2, and SRC-3 on female sexual behavior and steroid receptor-mediated transcription. Rat (r) SRC-1, rSRC-2, and rSRC-3 genes were cloned. Our results reveal a significant inhibitory effect by antisense (AS) to SRC-1 and SRC-2, but not SRC-3, on hormone-induced reproductive behavior. Importantly, sexual behavior was attenuated through estrogen receptor (ER)-dependent, rather than progesterone receptor (PR)-dependent, transcription, as E failed to induce the synthesis of PR content in the medial basal hypothalamus, and immunoreactive PR in the ventromedial nucleus were depleted in tissue from rSRC-1-AS- and rSRC-2-AS-treated, but not rSRC-3-AS-treated, rats primed with E. Consistent with interruption of ER-induced transcription, high dose of E and epidermal growth factor alone failed to induce sexual behavior in females treated with either rSRC-1-AS or SRC-2-AS. Immunoreactive SRC-1 and SRC-2, but not SRC-3, proteins were abundant in the ventromedial nucleus, thus demonstrating that the biological activities of hypothalamic steroid receptors are selectively regulated by regional distribution of specific SRCs. As SRC-1 knockout mice have only a slight loss in reproductive function, the possibility that genetic adaptation occurs during development was tested. Mouse (m) SRC-1-AS suppressed lordosis in wild-type, but not SRC-1, knockout mice, whereas mSRC-2-AS suppressed behavior in both genotypes. mSRC-3-AS had no effect in either genotype, and SRC-3 knockout mice exhibited full receptivity. Collectively, the findings clearly implicate dual regulation of ER-dependent function by SRC-1 and SRC-2 in the intact female brain. In the genetic, but not acute, absence of SRC-1, up-regulation of SRC-2 serves as a critical adaptive mechanism during female development.

This article has been cited by other articles:

				S. Lachize, E. M. Apostolakis, S. van der Laan, A. M. I. Tijssen, J. Xu, E. R. de Kloet, and O. C. Meijer Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids PNAS, May 12, 2009; 106(19): 8038 - 8042. [Abstract] [Full Text] [PDF]

				H. A. Molenda-Figueira, S. D. Murphy, K. L. Shea, N. K. Siegal, Y. Zhao, J. G. Chadwick Jr., L. A. Denner, and M. J. Tetel Steroid Receptor Coactivator-1 from Brain Physically Interacts Differentially with Steroid Receptor Subtypes Endocrinology, October 1, 2008; 149(10): 5272 - 5279. [Abstract] [Full Text] [PDF]

				J.-W. Jeong, K. Y. Lee, S. J. Han, B. J. Aronow, J. P. Lydon, B. W. O'Malley, and F. J. DeMayo The p160 Steroid Receptor Coactivator 2, SRC-2, Regulates Murine Endometrial Function and Regulates Progesterone-Independent and -Dependent Gene Expression Endocrinology, September 1, 2007; 148(9): 4238 - 4250. [Abstract] [Full Text] [PDF]

				M. Schumacher, R. Guennoun, A. Ghoumari, C. Massaad, F. Robert, M. El-Etr, Y. Akwa, K. Rajkowski, and E.-E. Baulieu Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System Endocr. Rev., June 1, 2007; 28(4): 387 - 439. [Abstract] [Full Text] [PDF]

				M. M White, I. Sheffer, J. Teeter, and E. M. Apostolakis Hypothalamic progesterone receptor-A mediates gonadotropin surges, self priming and receptivity in estrogen-primed female mice J. Mol. Endocrinol., January 1, 2007; 38(1): 35 - 50. [Abstract] [Full Text] [PDF]

				E. Karteris, S. Zervou, Y. Pang, J. Dong, E. W. Hillhouse, H. S. Randeva, and P. Thomas Progesterone Signaling in Human Myometrium through Two Novel Membrane G Protein-Coupled Receptors: Potential Role in Functional Progesterone Withdrawal at Term Mol. Endocrinol., July 1, 2006; 20(7): 1519 - 1534. [Abstract] [Full Text] [PDF]

				J. Grenier, A. Trousson, A. Chauchereau, J. Cartaud, M. Schumacher, and C. Massaad Differential Recruitment of p160 Coactivators by Glucocorticoid Receptor between Schwann Cells and Astrocytes Mol. Endocrinol., February 1, 2006; 20(2): 254 - 267. [Abstract] [Full Text] [PDF]

				E. M. Apostolakis, D. N. Riherd, and B. W. O'Malley PAC1 Receptors Mediate Pituitary Adenylate Cyclase-Activating Polypeptide- and Progesterone-Facilitated Receptivity in Female Rats Mol. Endocrinol., November 1, 2005; 19(11): 2798 - 2811. [Abstract] [Full Text] [PDF]

				T. D. Charlier, G. F. Ball, and J. Balthazart Inhibition of Steroid Receptor Coactivator-1 Blocks Estrogen and Androgen Action on Male Sex Behavior and Associated Brain Plasticity J. Neurosci., January 26, 2005; 25(4): 906 - 913. [Abstract] [Full Text] [PDF]

				P.-L. Xu, Y.-Q. Liu, S.-F. Shan, Y.-Y. Kong, Q. Zhou, M. Li, J.-P. Ding, Y.-H. Xie, and Y. Wang Molecular Mechanism for the Potentiation of the Transcriptional Activity of Human Liver Receptor Homolog 1 by Steroid Receptor Coactivator-1 Mol. Endocrinol., August 1, 2004; 18(8): 1887 - 1905. [Abstract] [Full Text] [PDF]

				E. Setiawan, D. Owen, L. McCabe, A. Kostaki, M. H. Andrews, and S. G. Matthews Glucocorticoids Do Not Alter Developmental Expression of Hippocampal or Pituitary Steroid Receptor Coactivator-1 and -2 in the Late Gestation Fetal Guinea Pig Endocrinology, August 1, 2004; 145(8): 3796 - 3803. [Abstract] [Full Text] [PDF]

				C. L. Smith and B. W. O'Malley Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators Endocr. Rev., February 1, 2004; 25(1): 45 - 71. [Abstract] [Full Text] [PDF]

				H. A. Molenda, C. P. Kilts, R. L. Allen, and M. J. Tetel Nuclear Receptor Coactivator Function in Reproductive Physiology and Behavior Biol Reprod, November 1, 2003; 69(5): 1449 - 1457. [Abstract] [Full Text] [PDF]

				J. Xu and Q. Li Review of the in Vivo Functions of the p160 Steroid Receptor Coactivator Family Mol. Endocrinol., September 1, 2003; 17(9): 1681 - 1692. [Abstract] [Full Text] [PDF]

				J. C. Condon, P. Jeyasuria, J. M. Faust, J. W. Wilson, and C. R. Mendelson A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition PNAS, August 5, 2003; 100(16): 9518 - 9523. [Abstract] [Full Text] [PDF]