title: Acute disruption of select steroid receptor coactivators prevents reproductive behavior in rats and unmasks genetic adaptation in knockout mice.
abstract: 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 alpha (ERalpha)-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 ERalpha-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 ERalpha-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.
authors.affiliation: Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA. edea@bcm.tmc.edu
authors.forename: Ede Marie
authors.initials: EM
authors.lastname: Apostolakis
authors.forename: Meera
authors.initials: M
authors.lastname: Ramamurphy
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Sergio
authors.initials: S
authors.lastname: Oñate
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D051548:Histone Acetyltransferases; D007033:Hypothalamus, Middle / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D012098:Reproduction; D012726:Sexual Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; C498003:Ncoa2 protein, rat; D051958:Nuclear Receptor Coactivator 2; D016376:Oligonucleotides, Antisense; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D015534:Trans-Activators; D014157:Transcription Factors; D011374:Progesterone; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; C538867:Ncoa3 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3