Publications (16)64.79 Total impact
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Article: Opposite-sex housing reactivates the declining GnRH system in aged transgenic male mice with FGF signaling deficiency.
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ABSTRACT: The continued presence of gonadotropin-releasing hormone (GnRH) neurons is required for a healthy reproductive lifespan, but factors that maintain postnatal GnRH neurons have not been identified. To begin to understand these factors, we investigated whether (1) fibroblast growth factor (FGF) signaling and (2) interactions with the opposite sex are involved in the maintenance of the postnatal GnRH system. A transgenic mouse model (dnFGFR mouse) with the targeted expression of a dominant-negative FGF receptor (dnFGFR) in GnRH neurons was used to examine the consequence of FGF signaling deficiency on postnatal GnRH neurons. Male dnFGFR mice suffered a significant loss of postnatal GnRH neurons within the first 100 days of life. Interestingly, this loss was reversed after cohabitation with female, but not male, mice for 300-550 days. Further, opposite sex housing in dnFGFR males also increased hypothalamic GnRH peptide levels, promoted a more mature GnRH neuronal morphology, facilitated litter production, and enhanced testicular morphology. Lastly, mice hypomorphic for FGFR3 exhibited a similar pattern of postnatal GnRH neuronal loss as dnFGFR males, suggesting FGF signaling acts, in part, through FGFR3 to enhance the maintenance of the postnatal GnRH system. In summary, we have shown that FGF signaling is required for the continued presence of postnatal GnRH neurons. However, this requirement is not absolute as sexual interactions can compensate for defects in FGFR signaling, thereby rescuing the declining GnRH system. This suggests the postnatal GnRH system is highly plastic and capable of responding to environmental stimuli throughout adult life.AJP Endocrinology and Metabolism 10/2012; · 4.75 Impact Factor -
Article: Fibroblast growth factor signaling deficiencies impact female reproduction and kisspeptin neurons in mice.
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ABSTRACT: Fibroblast growth factor (FGF) signaling is essential for the development of the gonadotropin-releasing hormone (GnRH) system. Mice harboring deficiencies in Fgf8 or Fgf receptor 1 (Fgfr1) suffer a significant loss of GnRH neurons, but their reproductive phenotypes have not been examined. This study examined if female mice hypomorphic for Fgf8, Fgfr1, or both (compound hypomorphs) exhibited altered parameters of pubertal onset, estrous cyclicity, and fertility. Further, we examined the number of kisspeptin (KP)-immunoreactive (ir) neurons in the anteroventral periventricular/periventricular nuclei (AVPV/PeV) of these mice to assess if changes in the KP system, which stimulates the GnRH system, could contribute to the reproductive phenotypes. Single hypomorphs (Fgfr1(+/-) or Fgf8(+/-)) had normal timing for vaginal opening (VO) but delayed first estrus. However, after achieving the first estrus, they underwent normal expression of estrous cycles. In contrast, the compound hypomorphs underwent early VO and normal first estrus, but had disorganized estrous cycles that subsequently reduced their fertility. KP immunohistochemistry on Postnatal Day 15, 30, and 60 transgenic female mice revealed that female compound hypomorphs had significantly more KP-ir neurons in the AVPV/PeV compared to their wild-type littermates, suggesting increased KP-ir neurons may drive early VO but could not maintain the cyclic changes in GnRH neuronal activity required for female fertility. Overall, these data suggest that Fgf signaling deficiencies differentially alter the parameters of female pubertal onset and cyclicity. Further, these deficiencies led to changes in the AVPV/PeV KP-ir neurons that may have contributed to the accelerated VO in the compound hypomorphs.Biology of Reproduction 01/2012; 86(4):119. · 4.01 Impact Factor -
Article: Fibroblast growth factor signaling in the developing neuroendocrine hypothalamus.
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ABSTRACT: Fibroblast growth factor (FGF) signaling is pivotal to the formation of numerous central regions. Increasing evidence suggests FGF signaling also directs the development of the neuroendocrine hypothalamus, a collection of neuroendocrine neurons originating primarily within the nose and the ventricular zone of the diencephalon. This review outlines evidence for a role of FGF signaling in the prenatal and postnatal development of several hypothalamic neuroendocrine systems. The emphasis is placed on the nasally derived gonadotropin-releasing hormone neurons, which depend on neurotrophic cues from FGF signaling throughout the neurons' lifetime. Although less is known about neuroendocrine neurons derived from the diencephalon, recent studies suggest they also exhibit variable levels of dependence on FGF signaling. Overall, FGF signaling provides a broad spectrum of cues that ranges from genesis, cell survival/death, migration, morphological changes, to hormone synthesis in the neuroendocrine hypothalamus. Abnormal FGF signaling will deleteriously impact multiple hypothalamic neuroendocrine systems, resulting in the disruption of diverse physiological functions.Frontiers in Neuroendocrinology 01/2011; 32(1):95-107. · 11.43 Impact Factor -
Article: Abnormal hypothalamic oxytocin system in fibroblast growth factor 8-deficient mice.
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ABSTRACT: Oxytocin (OT) is a nonapeptide essential for maternal care. The development of the OT neuroendocrine system is a multi-step process dependent on the action of many transcription factors, but upstream signaling molecules regulating this process are still poorly understood. In this study, we examined if fibroblast growth factor 8 (FGF8), a signaling molecule critical for forebrain development, is essential for the proper formation of the OT system. Using immunohistochemistry, we showed a significant reduction in the number of neurons immunoreactive for the mature OT peptide in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) in the hypothalamus of homozygous (HOMO) FGF8 hypomorphic mice compared to wild-type mice. The number of neurons positive for oxyphysin prohormone in the SON but not the PVN was also significantly reduced in FGF8 HOMO hypomorphs. However, steady-state mRNA levels of the oxyphysin prohormone were not significantly different between FGF8 hypomorphs and WT mice. These data suggest that a global reduction in FGF8 signaling leads to an overall reduction of mature OT and oxyphysin prohormone levels that may have resulted from defects in multiple stages of the hormone-synthesis pathway. Since proper hormone synthesis is a hallmark of mature OT neurons, this study suggests that FGF8 signaling may contribute to the phenotypic maturation of a neuroendocrine system that originates within the diencephalon.Endocrine 10/2010; 38(2):174-80. · 1.42 Impact Factor -
Article: Role of fibroblast growth factor signaling in gonadotropin-releasing hormone neuronal system development.
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ABSTRACT: There is growing evidence demonstrating that fibroblast growth factor (FGF) signaling is important for the development of the gonadotropin-releasing hormone (GnRH) neuronal system. In humans, loss-of-function mutations in FGF receptor 1 (Fgfr1) and Fgf8 lead to hypogonadotropic hypogonadism (HH) with or without anosmia. Insights into how FGF signaling deficiency disrupts the GnRH system in humans are beginning to emerge from studies using transgenic mouse models. In this review, we summarize GnRH system defects in several lines of FGF signaling-deficient mice. We showed that FGF signaling is critically required for olfactory placode induction, differentiation, and GnRH neuronal fate specification and postnatal maintenance. Extrapolating from these transgenic mouse data, we suggest that idiopathic HH in patients harboring loss-of-function Fgfr1 and/or Fgf8 mutations is not merely a result of defective GnRH neuronal migration, but also insults accumulated in the GnRH system during fate specification and postnatal development.Frontiers of hormone research 01/2010; 39:37-50. · 1.71 Impact Factor -
Article: Differential fibroblast growth factor 8 (FGF8)-mediated autoregulation of its cognate receptors, Fgfr1 and Fgfr3, in neuronal cell lines.
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ABSTRACT: Fibroblast growth factors (FGFs) mediate a vast range of CNS developmental processes including neural induction, proliferation, migration, and cell survival. Despite the critical role of FGF signaling for normal CNS development, few reports describe the mechanisms that regulate FGF receptor gene expression in the brain. We tested whether FGF8 could autoregulate two of its cognate receptors, Fgfr1 and Fgfr3, in three murine cell lines with different lineages: fibroblast-derived cells (3T3 cells), neuronal cells derived from hippocampus (HT-22 cells), and neuroendocrine cells derived from hypothalamic gonadotropin-releasing hormone (GnRH) neurons (GT1-7 cells). GnRH is produced by neurons in the hypothalamus and is absolutely required for reproductive competence in vertebrate animals. Several lines of evidence strongly suggest that Fgf8 is critical for normal development of the GnRH system, therefore, the GT1-7 cells provided us with an additional endpoint, Gnrh gene expression and promoter activity, to assess potential downstream consequences of FGF8-induced modulation of FGF receptor levels. Results from this study suggest that the autoregulation of its cognate receptor represents a common downstream effect of FGF8. Further, we show that Fgfr1 and Fgfr3 are differentially regulated within the same cell type, implicating these two receptors in different biological roles. Moreover, Fgfr1 and Fgfr3 are differentially regulated among different cell types, suggesting such autoregulation occurs in a cell type-specific fashion. Lastly, we demonstrate that FGF8b decreases Gnrh promoter activity and gene expression, possibly reflecting a downstream consequence of altered FGF receptor populations. Together, our data bring forth the possibility that, in addition to the FGF synexpression group, autoregulation of FGFR expression by FGF8 represents a mechanism by which FGF8 could fine-tune its regulatory actions.PLoS ONE 01/2010; 5(4):e10143. · 4.09 Impact Factor -
Article: Arginine vasopressin regulation in pre- and postpubertal male rats by the androgen metabolite 3beta-diol.
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ABSTRACT: Arginine vasopressin (AVP) is a nonapeptide expressed in several brain regions. In addition to its well-characterized role in osmoregulation, AVP regulates paternal behavior, aggression,circadian rhythms, and the stress response. In the bed nucleus of the stria terminalis (BST), AVP gene expression is tightly regulated by gonadal steroid hormones. However, the degree by which AVP is regulated by gonadal steroid hormones in the suprachiasmatic nucleus (SCN) and medial amygdala (MeA) is unclear. Previous studies have shown that AVP expression in the brain of gonadectomized rats is restored with testosterone, 17beta-estradiol, and 5alpha-dihydrotestosterone(DHT) replacement. In addition, we have demonstrated that 3beta-diol, a metabolite of DHT,increased AVP promoter activity in a neuronal cell line and that the effects of 3beta-diol on AVP promoter activity were mediated by estrogen receptor-beta. To test whether 3beta-diol has a physiological role in the regulation of central AVP expression in vivo, we gonadectomized pre- and postpubertal male rats and followed with once daily injections of estradiol benzoate (EB),DHT-propionate, 3beta-diol-dipropionate, or vehicle. The SCN, BST, and MeA were analyzed for AVP mRNA expression using in situ hybridization. In the BST, intact juveniles had significantly fewer AVP-expressing cells than adults. GDX abolished all AVP mRNA expression in the BST in both age groups, whereas treatment with EB restored >80% and DHTP <10% of the AVP expression. Interestingly, 3beta-diol-proprionate was more effective at inducing AVP expression in juveniles than in adults, suggesting that the regulation of AVP by 3beta-diol might be age dependent [corrected].AJP Endocrinology and Metabolism 05/2009; 296(6):E1409-13. · 4.75 Impact Factor -
Article: Fibroblast growth factor 8 signaling through fibroblast growth factor receptor 1 is required for the emergence of gonadotropin-releasing hormone neurons.
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ABSTRACT: GnRH neurons are essential for the onset and maintenance of reproduction. Mutations in both fibroblast growth factor receptor (Fgfr1) and Fgf8 have been shown to cause Kallmann syndrome, a disease characterized by hypogonadotropic hypogonadism and anosmia, indicating that FGF signaling is indispensable for the formation of a functional GnRH system. Presently it is unclear which stage of GnRH neuronal development is most impacted by FGF signaling deficiency. GnRH neurons express both FGFR1 and -3; thus, it is also unclear whether FGFR1 or FGFR3 contributes directly to GnRH system development. In this study, we examined the developing GnRH system in mice deficient in FGF8, FGFR1, or FGFR3 to elucidate the individual contribution of these FGF signaling components. Our results show that the early emergence of GnRH neurons from the embryonic olfactory placode requires FGF8 signaling, which is mediated through FGFR1, not FGFR3. These data provide compelling evidence that the developing GnRH system is exquisitely sensitive to reduced levels of FGF signaling. Furthermore, Kallmann syndrome stemming from FGF signaling deficiency may be due primarily to defects in early GnRH neuronal development prior to their migration into the forebrain.Endocrinology 07/2008; 149(10):4997-5003. · 4.46 Impact Factor -
Article: Detection and localization of an estrogen receptor beta splice variant protein (ERbeta2) in the adult female rat forebrain and midbrain regions.
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ABSTRACT: Estrogens regulate neural processes such as neuronal development, reproductive behavior, and hormone secretion, and signal through estrogen receptor (ER) alpha and ERbeta (here called ERbeta1). Recent studies have found variations in ERalpha and ERbeta1 mRNA splicing in rodents and humans. Functional reporter gene assays suggest that these splicing variations alter ER-mediated transcriptional regulation. Estrogen receptor beta 2 (ERbeta2), an ERbeta1 splice variant containing an 18 amino acid (AA) insert in the ligand binding domain, binds estradiol with approximately 10-fold lower affinity than ERbeta1, suggesting that it may serve as a low-affinity ER. Moreover, ERbeta2 reportedly acts in a dominant-negative fashion when heterodimerized with ERbeta1 or ERalpha. To explore the function of ERbeta2 in brain, an antiserum (TwobetaER.1) targeting the 18 AA insert was developed and characterized. Western blot analysis and transient expression of ERbeta2 in cell lines demonstrated that TwobetaER.1 recognizes ERbeta2. In the adult female rat brain, ERbeta2 immunoreactivity is localized in the cell nucleus and is expressed with a distribution similar to that of ERbeta1 mRNA. ERbeta2 immunoreactive cell numbers were high in, for example, piriform cortex, paraventricular nucleus, supraoptic nucleus, arcuate nucleus, and hippocampal CA regions, whereas it was low in the dentate gyrus. Moreover, ERbeta2 is coexpressed in gonadotropin-releasing hormone and oxytocin neurons. These studies demonstrate ERbeta splice variant proteins in brain and support the hypothesis that ER signaling diversity depends not only on ligand or coregulatory proteins, but also on regional and phenotypic selectivity of ER splice variant proteins.The Journal of Comparative Neurology 12/2007; 505(3):249-67. · 3.81 Impact Factor -
Article: Detection and localization of an estrogen receptor beta splice variant protein (ERβ2) in the adult female rat forebrain and midbrain regions
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ABSTRACT: Estrogens regulate neural processes such as neuronal development, reproductive behavior, and hormone secretion, and signal through estrogen receptor (ER) α and ERβ (here called ERβ1). Recent studies have found variations in ERα and ERβ1 mRNA splicing in rodents and humans. Functional reporter gene assays suggest that these splicing variations alter ER-mediated transcriptional regulation. Estrogen receptor beta 2 (ERβ2), an ERβ1 splice variant containing an 18 amino acid (AA) insert in the ligand binding domain, binds estradiol with ≈10-fold lower affinity than ERβ1, suggesting that it may serve as a low-affinity ER. Moreover, ERβ2 reportedly acts in a dominant-negative fashion when heterodimerized with ERβ1 or ERα. To explore the function of ERβ2 in brain, an antiserum (TwoβER.1) targeting the 18 AA insert was developed and characterized. Western blot analysis and transient expression of ERβ2 in cell lines demonstrated that TwoβER.1 recognizes ERβ2. In the adult female rat brain, ERβ2 immunoreactivity is localized in the cell nucleus and is expressed with a distribution similar to that of ERβ1 mRNA. ERβ2 immunoreactive cell numbers were high in, for example, piriform cortex, paraventricular nucleus, supraoptic nucleus, arcuate nucleus, and hippocampal CA regions, whereas it was low in the dentate gyrus. Moreover, ERβ2 is coexpressed in gonadotropin-releasing hormone and oxytocin neurons. These studies demonstrate ERβ splice variant proteins in brain and support the hypothesis that ER signaling diversity depends not only on ligand or coregulatory proteins, but also on regional and phenotypic selectivity of ER splice variant proteins. J. Comp. Neurol. 505:249–267, 2007. © 2007 Wiley-Liss, Inc.The Journal of Comparative Neurology 11/2007; 505(3):249 - 267. · 3.81 Impact Factor -
Article: Estrogen receptor-beta mediates dihydrotestosterone-induced stimulation of the arginine vasopressin promoter in neuronal cells.
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ABSTRACT: Arginine vasopressin (AVP) is a neuropeptide involved in the regulation of fluid balance, stress, circadian rhythms, and social behaviors. In the brain, AVP is tightly regulated by gonadal steroid hormones in discrete regions with gonadectomy abolishing and testosterone replacement restoring normal AVP expression in adult males. Previous studies demonstrated that 17beta-estradiol, a primary metabolite of testosterone, is responsible for restoring most of the AVP expression in the brain after castration. However, 5alpha-dihydrotestosterone (DHT) has also been shown to play a role in the regulation of AVP expression, thus implicating the involvement of both androgen and estrogen receptors (ER). Furthermore, DHT, through its conversion to 5alpha-androstane-3beta,17beta-diol, has been shown to modulate estrogen response element-mediated promoter activity through an ER pathway. The present study addressed two central hypotheses: 1) that androgens directly modulate AVP promoter activity and 2) the effect is mediated by an estrogen or androgen receptor pathway. To that end, we overexpressed androgen receptor, ERbeta, and ERbeta splice variants in a neuronal cell line and measured AVP promoter activity using a firefly luciferase reporter assay. Our results demonstrate that DHT and its metabolite 5alpha-androstane-3beta,17beta-diol stimulate AVP promoter activity through ERbeta in a neuronal cell line.Endocrinology 08/2007; 148(7):3371-82. · 4.46 Impact Factor -
Article: Ligand-independent effects of estrogen receptor beta on mouse gonadotropin-releasing hormone promoter activity.
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ABSTRACT: GnRH is the most upstream regulator of reproduction in vertebrates, and its synthesis and release are regulated by gonadal steroid hormones. The proposed sites of hormone action were historically thought to be upstream from GnRH neurons; however, the discovery of ERbeta in a subset of GnRH neurons suggests that this hypothesis should be reevaluated. To determine a functional role for ERbeta in GnRH neurons, we examined ERbeta's regulation of GnRH promoter activity. The GnRH-producing cell line, GT1-7, was cotransfected with expression vectors containing one of three ERbeta splice variants and a luciferase-reporter construct containing the full-length mouse GnRH promoter sequence or one of two deletions upstream of the transcription start site (-225/-201; -184/-150). Transfected cells were treated with 100 nm 17beta-estradiol (E(2)), diarylpropionitrile, raloxifene, or vehicle. There was a robust increase in GnRH-luciferase activity by all ERbeta splice variants in the absence of hormone. Furthermore, E(2) treatment abolished this response for ER-beta1 and ER-beta2, but not ER-beta1delta3. The -225/-201 and -184/-150 regions were critical for ERbeta-induced promoter activity because deletion of these regions eliminated the ligand-independent effects of ERbeta. ER-beta1 binds directly to these promoter regions and because there are no classical estrogen response elements in the mouse GnRH promoter, these data raise the possibility that this region contains a novel estrogen response element specific for ERbeta. Overall, our data suggest that ERbeta functions as a basic transcription factor in GnRH neurons and demonstrate a potential molecular mechanism for the negative feedback effects of E(2) on GnRH.Endocrinology 05/2006; 147(4):1924-31. · 4.46 Impact Factor -
Article: Progestin receptor expression in the developing rat brain depends upon activation of estrogen receptor alpha and not estrogen receptor beta.
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ABSTRACT: Perinatal 17beta-estradiol (E2) rapidly and markedly affects the morphological and neurochemical organization of the vertebrate brain. For instance, the sex difference in perinatal progestin receptor (PR) immunoreactivity in the medial preoptic nucleus (MPN) of the rat brain is due to the intracellular conversion of testosterone into E2 in males. Neonatal alpha-fetoprotein prevents circulating estrogens from accessing the brain, therefore, to overcome alpha-fetoprotein sequestration of E2, estrogen replacement studies during development have used natural and synthetic estrogen dosages in the milligram to microgram range. These levels could be considered as supraphysiological. Moreover, it is not clear through which ER subtype E2 acts to induce PR expression in the neonatal rat MPN because E2 binds similarly to estrogen receptor (ER)alpha and ERbeta. Consequently, we investigated whether nanogram levels of E2 affected PR protein and mRNA levels in the neonatal MPN. Furthermore, propylpyrazole-triol (PPT), a highly selective agonist for ERalpha, and diarylpropionitrile (DPN), a highly selective agonist for ERbeta, were used to determine if E2-dependent PR expression in the neonatal rat is mediated through ERalpha and/or ERbeta. Immunocytochemistry and quantitative real-time RT-PCR determined that as little as 100 ng E2 significantly induced PR protein and mRNA in the female and neonatally castrated male MPN on PN 4, indicating that the neonatal rat brain is highly sensitive to circulating estrogens. PPT, but not DPN, induced PR expression in the neonatal MPN and arcuate nucleus (Arc), demonstrating that PR expression in the neonatal rat brain depends solely on E2 activated ERalpha. In the lateral bed nucleus of the stria terminalis (BSTL), neither PPT nor DPN affected PR expression, suggesting the presence of a gonadal hormone-independent PR regulatory mechanism.Brain Research 05/2006; 1082(1):50-60. · 2.73 Impact Factor -
Article: The androgen metabolite, 5alpha-androstane-3beta, 17beta-diol, is a potent modulator of estrogen receptor-beta1-mediated gene transcription in neuronal cells.
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ABSTRACT: 5alpha-Androstane-3beta, 17beta-diol (3betaAdiol) is a metabolite of the potent androgen, 5alpha-dihydrotestosterone. Recent studies showed that 3betaAdiol binds to estrogen receptor (ER)-beta and regulates growth of the prostate gland through an estrogen, and not androgen, receptor-mediated pathway. These data raise the possibility that 3betaAdiol could regulate important physiological processes in other tissues that produce 3betaAdiol, such as the brain. Although it is widely accepted that the brain is a target for 5alpha-dihydrotestosterone action, there is no evidence that 3betaAdiol has a direct action in neurons. To explore the molecular mechanisms by which 3betaAdiol might act to modulate gene transcription in neuronal cells, we examined whether 3betaAdiol activates ER-mediated promoter activity and whether ER transactivation is facilitated by a classical estrogen response element (ERE) or an AP-1 complex. The HT-22 neuronal cell line was cotransfected with an expression vector containing ERalpha, ER-beta1, or the ERbeta splice variant, ER-beta2 and one of two luciferase-reporter constructs containing either a consensus ERE or an AP-1 enhancer site. Cells were treated with 100 nM 17beta-estradiol, 100 nM 3betaAdiol, or vehicle for 15 h. We show that 3betaAdiol activated ER-beta1-induced transcription mediated by an ERE equivalent to that of 17beta-estradiol. By contrast, 3betaAdiol had no effect on ERalpha- or ER-beta2-mediated promoter activity. Moreover, ER-beta1 stimulated transcription mediated by an ERE and inhibited transcription by an AP-1 site in the absence of ligand binding. These data provide evidence for activation of ER signaling pathways by an androgen metabolite in neuronal cells.Endocrinology 02/2005; 146(1):147-55. · 4.46 Impact Factor -
Article: Novel actions of estrogen receptor-beta on anxiety-related behaviors.
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ABSTRACT: Estrogens are reported to have both anxiogenic and anxiolytic properties. This dichotomous neurobiological response to estrogens may be mediated by the existence of two distinct estrogen receptor (ER) systems, ERalpha and ERbeta. In brain, ERalpha plays a critical role in regulating reproductive neuroendocrine function, whereas ERbeta may be more important in regulating nonreproductive functions. To determine whether estrogen's anxiolytic actions could be mediated by ERbeta, we examined anxiety-related behaviors after treatment with ER subtype-selective agonists. Ovariectomized female rats, divided into four treatment groups, were injected with the selective ERbeta agonist diarylpropionitrile (DPN), the ERalpha-selective agonist propyl-pyrazole-triol (PPT), 17beta-estradiol, or vehicle daily for 4d. After injections, behavior was monitored in the elevated plus maze or open field. Rats treated with DPN showed significantly decreased anxiety-related behaviors in both behavioral paradigms. In the elevated plus maze, DPN significantly increased the number of open arm entries and time spent on the open arms of the maze. Furthermore, DPN significantly reduced, whereas PPT increased, anxiogenic behaviors such as the number of fecal boli and time spent grooming. In the open field, DPN-treated females made more rears, interacted more with a novel object, and spent more time in the middle of the open field than did control or PPT-treated rats. To confirm that DPN's anxiolytic actions are ER mediated, the nonselective ER antagonist tamoxifen was administered alone or in combination with DPN. Tamoxifen blocked the previously identified anxiolytic actions of DPN. Taken together, these findings suggest that the anxiolytic properties of estrogens are ERbeta mediated.Endocrinology 02/2005; 146(2):797-807. · 4.46 Impact Factor -
Article: Progestin receptor expression in the developing rat brain depends upon activation of estrogen receptor α and not estrogen receptor β
[show abstract] [hide abstract]
ABSTRACT: Perinatal 17β-estradiol (E2) rapidly and markedly affects the morphological and neurochemical organization of the vertebrate brain. For instance, the sex difference in perinatal progestin receptor (PR) immunoreactivity in the medial preoptic nucleus (MPN) of the rat brain is due to the intracellular conversion of testosterone into E2 in males. Neonatal α-fetoprotein prevents circulating estrogens from accessing the brain, therefore, to overcome α-fetoprotein sequestration of E2, estrogen replacement studies during development have used natural and synthetic estrogen dosages in the milligram to microgram range. These levels could be considered as supraphysiological. Moreover, it is not clear through which ER subtype E2 acts to induce PR expression in the neonatal rat MPN because E2 binds similarly to estrogen receptor (ER)α and ERβ. Consequently, we investigated whether nanogram levels of E2 affected PR protein and mRNA levels in the neonatal MPN. Furthermore, propylpyrazole-triol (PPT), a highly selective agonist for ERα, and diarylpropionitrile (DPN), a highly selective agonist for ERβ, were used to determine if E2-dependent PR expression in the neonatal rat is mediated through ERα and/or ERβ. Immunocytochemistry and quantitative real-time RT-PCR determined that as little as 100 ng E2 significantly induced PR protein and mRNA in the female and neonatally castrated male MPN on PN 4, indicating that the neonatal rat brain is highly sensitive to circulating estrogens. PPT, but not DPN, induced PR expression in the neonatal MPN and arcuate nucleus (Arc), demonstrating that PR expression in the neonatal rat brain depends solely on E2 activated ERα. In the lateral bed nucleus of the stria terminalis (BSTL), neither PPT nor DPN affected PR expression, suggesting the presence of a gonadal hormone-independent PR regulatory mechanism.Brain Research.
Top co-authors
Top Journals
Institutions
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2008–2012
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University of Colorado at Boulder
Boulder, CO, USA
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2009
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Loyola University Chicago
- Stritch School of Medicine
Chicago, IL, USA
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2005–2007
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Colorado State University
- Department of Biomedical Sciences
Fort Collins, CO, USA
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