[Show abstract][Hide abstract] ABSTRACT: The first appearance, distribution and frequency of immunoglobulins (Igs)-positive lymphocytes were investigated in the lymphoid organs of native chicken’s embryos from embryonic day (ED) 8 to ED 20. The tissues from the lymphoid organs were dehydrated in alcohol, cleared in xylene, embedded in different grades of paraffin and 6-micron thick sections were immunostained by the indirect immunoperoxidase method using antichicken immunoglobulins. IgM-positive lymphocytes were first identified in the follicles of bursa of Fabricius at ED 10, in the white pulp of the spleen at ED 14 and in the lamina propria of the cecal tonsil at ED 20. Their frequencies of populations were statistically significant from ED 14 to ED 20. IgG-positive lymphocytes were first appeared in the bursa of Fabricius and spleen at ED 20. In the bursa IgG-positive lymphocytes were located in the medulla and cortical part of the follicles, whereas, in the spleen these immune cells were located around the white pulp. IgA-positive lymphocytes were not observed in any of the developing lymphoid organs of the present study. When the data for bursa of Fabricius, spleen, thymus and cecal tonsil were statistically compared, it was observed that both IgM- and IgG-positive lymphocytes were significantly higher in bursa of Fabricius.
International Journal of Veterinary Science and Medicine. 12/2013;
[Show abstract][Hide abstract] ABSTRACT: Huntingtin-associated protein 1 (HAP1) is a neural huntingtin interactor that is widely expressed as a core molecule of the stigmoid body (a neurocytoplasmic inclusion) in the limbic and hypothalamic regions and has putative protective functions against some neurodegenerative diseases (HAP1 protection hypothesis). Although HAP1 has been reported to be intimately associated with several steroid receptors, HAP1-immunoreactive (HAP1-ir) cells remain to be identified in the hippocampus, which is one of the major steroidal targets. In this study, we determined the distribution of hippocampal HAP1-ir cells in light and fluorescence microscopy and characterized their morphological relationships with steroid receptors, markers of adult neurogenesis, and the GABAergic system in adult male and female Wistar rats. HAP1-ir cells, which were sporadically distributed particularly in the subgranular zone (SGZ) of the dentate gyrus and in the interface between the stratum lacunosum-moleculare and stratum radiatum of Ammon's horn, were identified as the "sporadically lurking HAP1-ir (SLH)" cells. The SLH cells showed no clear association with neural progenitor/proliferating or migrating cell markers of adult neurogenesis, such as Ki-67, proliferating cell nuclear antigen, doublecortin, and glial fibrillary acidic protein in the SGZ, whereas all the SLH cells expressed a neuronal specific nuclear protein (NeuN). More than 90% of the SLH cells expressed nuclear estrogen receptor (ER) α but neither ERβ nor the androgen receptor, whereas glucocorticoid receptor was differently stained in the SLH cells depending on the antibodies. More than 60% of them exhibited GABA immunoreactivity in the SGZ, suggestive of basket cells, but they were distinct from the ones expressing cholecystokinin or parvalbumin. We conclude that SLH cells, which should be stable against apoptosis due to putative HAP1 protectivity, might be involved in estrogen-dependent maturation, remodeling and activation of hippocampal memory and learning functions via ERα and partly through GABAergic regulation.
[Show abstract][Hide abstract] ABSTRACT: The stigmoid body (STB) is a cytoplasmic inclusion containing huntingtin-associated protein 1 (HAP1), and HAP1/STB formation is induced by transfection of the HAP1 gene into cultured cells. In the present study, we examined the intracellular colocalization of HAP1/STBs with steroid hormone receptors (SHRs), including the androgen receptor (AR), estrogen receptor, glucocorticoid receptor (GR), and mineralocorticoid receptor, in COS-7 cells cotransfected with HAP1 and each receptor. We found that C-terminal ligand-binding domains of all SHRs had potential for colocalization with HAP1/STBs, whereas only AR and GR were clearly colocalized with HAP1/STBs when each full-length SHR was coexpressed with HAP1. In addition, it appeared that HAP1/STBs did not disrupt GR and AR functions because the receptors on HAP1/STBs maintained nuclear translocation activity in response to their specific ligands. When the cells were treated with a proteasome inhibitor, GR and AR localized outside HAP1/STBs translocated into the nucleus, whereas the receptors colocalized with HAP1/STBs persisted in their colocalization even after treatment with their ligands. Therefore, HAP1/STBs may be involved in cytoplasmic modifications of the nuclear translocation of GR and AR in a ubiquitin-proteasome system.
Experimental Cell Research 07/2011; 317(12):1689-700. · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Wolfram syndrome is an autosomal recessive disorder characterized by juvenile-onset insulin-dependent diabetes mellitus and optic atrophy. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER) resident transmembrane protein. The Wfs1-null mouse exhibits progressive insulin deficiency causing diabetes. Previous work suggested that the function of the WFS1 protein is connected to unfolded protein response and to intracellular Ca(2+) homeostasis. However, its precise molecular function in pancreatic β-cells remains elusive. In our present study, immunofluorescent and electron-microscopic analyses revealed that WFS1 localizes not only to ER but also to secretory granules in pancreatic β-cells. Intragranular acidification was assessed by measuring intracellular fluorescence intensity raised by the acidotrophic agent, 3-[2,4-dinitroanilino]-3'-amino-N-methyldipropyramine. Compared with wild-type β-cells, there was a 32% reduction in the intensity in WFS1-deficient β-cells, indicating the impairment of granular acidification. This phenotype may, at least partly, account for the evidence that Wfs1-null islets have impaired proinsulin processing, resulting in an increased circulating proinsulin level. Morphometric analysis using electron microscopy evidenced that the density of secretory granules attached to the plasma membrane was significantly reduced in Wfs1-null β-cells relative to that in wild-type β-cells. This may be relevant to the recent finding that granular acidification is required for the priming of secretory granules preceding exocytosis and may partly explain the fact that glucose-induced insulin secretion is profoundly impaired in young prediabetic Wfs1-null mice. These results thus provide new insights into the molecular mechanisms of β-cell dysfunction in patients with Wolfram syndrome.
Human Molecular Genetics 03/2011; 20(7):1274-84. · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Huntingtin-associated protein 1 (HAP1) is an essential component of the stigmoid body (STB) and known as a possible neuroprotective interactor with causative proteins for Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar ataxia type 17 (SCA17), and Joubert syndrome. To clarify what other causative molecules HAP1/STB could interact with, we cloned normal causative genes for several neural disorders from human brain RNA library and evaluated their subcellular interaction with HAP1/STB by immunocytochemistry and immunoprecipitation after cotransfection into Neuro2a cells. The results clearly showed that HAP1/STB interacts with the normal ataxin-3 through Josephin domain and polyglutamine-expanded mutants derived from SCA3 as well. The findings suggest that HAP1/STB could modify the physiological function of normal ataxin-3 and pathogenesis of SCA3 attributable to the mutant ataxin-3.
[Show abstract][Hide abstract] ABSTRACT: The stigmoid body (STB) is a neurocytoplasmic inclusion containing huntingtin-associated protein 1 (HAP1), an interactor of huntingtin, and its formation is induced by transfection of HAP1-cDNA into cultured cells. Although STB is believed to play a protective role in polyglutamine diseases, including Huntington's disease and spinal and bulbar muscular atrophy, by sequestering the causative proteins, huntingtin and androgen receptor, respectively, its physiological function and formation remain poorly understood. Therefore, STB is occasionally confused with another cytoplasmic inclusion observed in polyglutamine diseases, the aggresome. Here we examined the subcellular dynamics of STB and compared it immunohistochemically and cytochemically with the aggresome in the rat brain and COS-7 or HeLa cells transfected with HAP1 and/or polyglutamine disease-associated genes. In time-lapse image analysis of HAP1-transfected cells, the HAP1-induced STB is formed from multiple fusions of small HAP1 inclusions characterized by vigorous cytoplasmic movement. In HAP1-transfected cells treated with a microtubule-depolymerizing drug, although the formation of small HAP1 inclusions was not affected, their fusion was critically inhibited. Immunohistochemistry and cytochemistry revealed the absence of association between STB and aggresomal markers, such as ubiquitin/proteasome, intermediate filaments, and the centrosome. Taken together, we concluded that STB is formed by a two-step process comprising microtubule-independent formation of small HAP1 inclusions and microtubule-dependent fusion of these inclusions, and that STB is distinct from pathological aggresomes.
[Show abstract][Hide abstract] ABSTRACT: Wolfram syndrome is a rare genetic disorder accompanying diabetes insipidus, sensorineural hearing loss, neurological complications, and psychiatric illness. This syndrome has been attributed to mutations in the WFS1 gene. In this study, we made a detailed histochemical analysis of the distribution of Wfs1 mRNA in the brain of developing mice. There were three patterns of change in the strength of Wfs1 mRNA signals from birth to early adulthood. In type 1, the signals were weak or absent in neonates but strong or moderate in young adults. This pattern was observed in the CA1 field, parasubiculum, and entorhinal cortex. In type 2, the signals were of a relatively constant strength during development. This pattern was seen in limbic structures (e.g. subiculum and central amygdaloid nucleus) and brainstem nuclei (e.g. facial and chochlear nuclei). In type 3, the signals peaked in the second week of age. This pattern was observed in the thalamic reticular nucleus. Thus, Wfs1 mRNA was widely distributed in the normal mouse brain during postnatal development. This evidence may provide clues as to the physiological role of the Wfs1 gene in the central nervous system, and help to explain endocrinological, otological, neurological, and psychiatric symptoms in Wolfram syndrome patients.
Neuroscience Research 07/2009; 64(2):213-30. · 2.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death.
We studied the effect of breeding Wfs1 ( -/- ) mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A ( y ) /a). We also treated the mice with pioglitazone.
Wfs1 ( -/- ) mice bred on a C57BL/6J background rarely develop overt diabetes by 24 weeks of age, showing only mild beta cell loss. However, Wfs1 ( -/- ) A ( y ) /a mice developed selective beta cell loss and severe insulin-deficient diabetes as early as 8 weeks. This beta cell loss was due to apoptosis. In Wfs1 ( +/+ ) A ( y ) /a islets, levels of ER chaperone immunoglobulin-binding protein (BiP)/78 kDa glucose-regulated protein (GRP78) and phosphorylation of eukaryotic translation initiation factor 2, subunit alpha (eIF2alpha) apparently increased. Levels of both were further increased in Wfs1 ( -/- ) A ( y ) /a murine islets. Electron micrography revealed markedly dilated ERs in Wfs1 (-/-) A ( y ) /a murine beta cells. Interestingly, pioglitazone treatment protected beta cells from apoptosis and almost completely prevented diabetes development.
Wfs1-deficient beta cells are susceptible to ER stress. Increased insulin demand prompts apoptosis in such cells in vivo. Pioglitazone, remarkably, suppresses this process and prevents diabetes. As common WFS1 gene variants have recently been shown to confer a risk of type 2 diabetes, our findings may be relevant to the gradual but progressive loss of beta cells in type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Confocal laser scanning microscope image of double immunostaining for Wfs1 protein (green) and for glial fibrillary acidic protein (GFAP; an astrocyte marker; red) in the normal mouse retina and optic nerve. Cell nuclei are labeled in blue. The Wfs1 protein, also called wolframin, is the Wolfram syndrome 1 (Wfs1) gene product. Wfs1 is the disease gene for Wolfram syndrome, a neurodegenerative disorder defined by insulin-dependent diabetes mellitus and progressive optic atrophy. This image shows that Wfs1 immunoreactivity is observed in the GFAP-rich part of the optic nerve immediately behind the eye (central part of the image), and in most of the retinal layers (lower part of the image). J. Comp. Neurol. 510:1-23, 2008. (c) 2008 Wiley-Liss, Inc.
The Journal of Comparative Neurology 10/2008; 510(1):SPC1. · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neuronal aromatase, the enzyme that catalyzes the conversion of androgens to estrogens, is involved in brain sexual differentiation, the regulation of reproductive behavior, and gonadotropin secretion. We have previously reported that aromatase P450 (AromP450) protein expression is enhanced by both androgens and estrogens in the principal nucleus of the bed nucleus of the stria terminalis (prBST) and posterodorsal part of the medial amygdaloid nucleus (pdMAm) of the adult rat but is not altered in the central amygdaloid nucleus (CeAm) even after sex-steroid withdrawal or supplementation. Here, we have evaluated, via in situ hybridization with digoxigenin-labeled cRNA probes, the sex-steroidal regulation of brain AromP450 mRNA in the prBST, pdMAm, and CeAm of orchidectomized and adrenalectomized adult male rats treated with sesame oil, testosterone (1 mg/rat/day), dihydrotestosterone (1 mg/rat/day), or 17beta-estradiol (2 microg/rat/day) for 6 days. AromP450-mRNA expression in the prBST and pdMAm was markedly reduced in orchidectomized/adrenalectomized rats treated with sesame oil but strongly enhanced by testosterone or dihydrotestosterone and significantly reinstated by 17beta-estradiol. These results are essentially consistent with those of AromP450 protein expression and thus indicate that enhanced AromP450-protein expression in the prBST and pdMAm reflects transcriptional upregulation and/or post-transcriptional stabilization of its mRNA by sex steroids. In the CeAm, despite moderate AromP450-protein expression, the mRNA has never been detected with or without sex-steroidal manipulations, indicating that the putative sex-steroid-insensitive AromP450 mRNA in the CeAm may be distinct from that in the prBST and pdMAm or, if it occurs at all, expressed at much lower levels.
Cell and Tissue Research 07/2008; 332(3):381-91. · 3.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The anti-serum against an unknown human placental antigen complex X-P2 (hPAX-P2) immunohistochemically recognizes three putative molecules (hPAX-P2S, hPAX-P2N, and hPAX-P2R), each of which is associated with the stigmoid bodies (STBs), necklace olfactory glomeruli (NOGs), or reticulo-filamentous structures (RFs) in the rat brain. The STBs also contain huntingtin-associated protein 1 (HAP1), and the HAP1-cDNA transfection induces STB-like inclusions in cultured cells. In order to clarify the relationship between hPAX-P2S and HAP1 isoforms (A/B), we performed Western blotting, immuno-histo/cytochemistry for light- and electron-microscopy and pre-adsorption tests with HAP1 deletion fragments. The results showed that the anti-hPAX-P2 anti-serum recognizes HAP1(474-577) of HAP1A/B in Western blotting and strongly immunostains HAP1A-induced STB-like inclusions but far weakly detects HAP1B-induced diffuse structures in HAP1-transfected HEK 293 cells. In the rat brain, immunoreactivity of the anti-hPAX-P2 anti-serum for the STBs was eliminated by pre-adsorption with HAP1(474-577), whereas no pre-adsorption with any different HAP1 fragments can suppress immunoreactivity for the NOGs and RFs, which were not immunoreactive to anti-HAP1 anti-serum. These findings indicate that hPAX-P2S, which is distinct from hPAX-P2N and hPAX-P2R, is identical with STB-constituted HAP1 and that the HAP1-induced/immunoreactive inclusions correspond to the hPAX-P2-immunoreactive STBs previously identified in the brain.
[Show abstract][Hide abstract] ABSTRACT: The brain has an estrogen-biosynthetic potential resulting from the presence of neuronal aromatase, which controls the intraneural sex-steroidal milieu and is involved in brain sexual differentiation, psychobehavioral regulation, and neuroprotection. In the rat brain, three distinct aromatase-P450-immunoreactive (AromP450-I) neural groups have been categorized in terms of their peak expression time (fetal, fetoneonatal, and young-to-adult groups), suggesting the presence of region-specific regulation on brain AromP450. In the present study, we compared the expressions between AromP450 protein and mRNA by using immunohistochemistry and in situ hybridization with an ovary-derived cRNA probe in serial sections of fetal, fetoneonatal, and adult male rat brains and then performed steroidal manipulations to evaluate the sex-steroidal effects on AromP450 in adult orchiectomized and adrenalectomized (OCX + ADX) male rats. As a result, prominent mRNA signals were detected in the fetal (i.e., the anterior medial preoptic nucleus) and fetoneonatal (i.e., the medial preopticoamygdaloid neuronal arc) groups, although no detectable signal was found in the "young-to-adult" group (i.e., the central amygdaloid nucleus). In addition, the "fetoneonatal" AromP450-I neurons were prominently reduced in number and intensity after OCX + ADX and then were reinstated by the administration of dihydrotestosterone, testosterone, or 17beta-estradiol. In contrast, none of the sex steroids had any significant effects on the young-to-adult group. Several possible explanations were explored for why the young-to-adult group may differ in aromatase expression and regulation, including the possibility that distinct splicing variants or isozymes for aromatase exist in the rat brain.
The Journal of Comparative Neurology 02/2007; 500(3):557-73. · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, GPR30 was reported to be a novel estrogen receptor; however, its intracellular localization has remained controversial. To investigate the intracellular localization of GPR30 in vivo, we produced four kinds of polyclonal antibodies for distinct epitopes on GPR30. Immunocytochemical observations using anti-GPR30 antibody and anti-FLAG antibody show that FLAG-GPR30 localizes to the plasma membrane 24 h after transfection. Treatment with estrogen (17beta-estradiol or E2) causes an elevation in the intracellular Ca2+ concentration ([Ca2+]i) within 10 s in HeLa cells expressing FLAG-GPR30. In addition, E2 induces the translocation of GPR30 from the plasma membrane to the cytoplasm by 1 h after stimulation. Immunohistochemical analysis shows that GPR30 exists on the cell surface of CA2 pyramidal neuronal cells. The images on transmission electron microscopy show that GPR30 is localized to a particular region associated with the plasma membranes of the pyramidal cells. These data indicate that GPR30, a transmembrane receptor for estrogen, is localized to the plasma membrane of CA2 pyramidal neuronal cells of the hippocampus in rat brain.
Biochemical and Biophysical Research Communications 09/2006; 346(3):904-10. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Huntingtin-associated protein 1 (HAP1), an interactor of huntingtin, has been known as an essential component of the stigmoid body (STB) and recently reported to play a protective role against neurodegeneration in Huntington's disease (HD). In the present study, subcellular association between HAP1 and androgen receptor (AR) with a long polyglutamine tract (polyQ) derived from spinal-and-bulbar-muscular-atrophy (SBMA) was examined using HEp-2 cells cotransfected with HAP1 and/or normal ARQ25, SBMA-mutant ARQ65 or deletion-mutant AR cDNAs. The results provided the first clear evidence that HAP1 interacts with AR through its ligand-binding domain in a polyQ-length-dependent manner and forms prominent inclusions sequestering polyQ-AR, and that addition of dihydrotestosterone reduces the association strength of HAP1 with ARQ25 more dramatically than that with ARQ65. Furthermore, SBMA-mutant-ARQ65-induced apoptosis was suppressed by cotransfection with HAP1. Our findings strongly suggest that HAP1/STB is relevant to polyQ-length-dependent modification on subcellular AR functions and critically involved in pathogenesis of not only HD but also SBMA as an important intrinsic neuroprotectant determining the threshold for cellular vulnerability to apoptosis. Taking together with previous reports that HAP1/STB is selectively expressed in the brain regions spared from degenerative targets in HD and SBMA, the current study might explain the region-specific occurrence of neurodegeneration in both diseases, shedding light on common aspects of their molecular pathological mechanism and yet-to-be-uncovered diagnostic or therapeutic applications for HD and SBMA patients.
Human Molecular Genetics 09/2006; 15(15):2298-312. · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein. Homozygous WFS1 gene mutations cause Wolfram syndrome, characterized by insulin-deficient diabetes mellitus and optic atropy. Pancreatic beta-cells are selectively lost from the patient's islets. ER localization suggests that WFS1 protein has physiological functions in membrane trafficking, secretion, processing and/or regulation of ER calcium homeostasis. Disturbances or overloading of these functions induces ER stress responses, including apoptosis. We speculated that WFS1 protein might be involved in these ER stress responses.
Islet expression of the Wfs1 protein was analyzed immunohistochemically. Induction of Wfs1 upon ER stress was examined by Northern and Western blot analyses using three different models: human skin fibroblasts, mouse pancreatic beta-cell-derived MIN6 cells, and Akita mouse-derived Ins2 (96Y/Y) insulinoma cells. The human WFS1 gene promoter-luciferase reporter analysis was also conducted.
Islet beta-cells were the major site of Wfs1 expression. This expression was also found in delta-cells, but not in alpha-cells. WFS1 expression was transcriptionally up-regulated by ER stress-inducing chemical insults. Treatment of fibroblasts and MIN6 cells with thapsigargin or tunicamycin increased WFS1 mRNA. WFS1 protein also increased in response to thapsigargin treatment in these cells. WFS1 gene expression was also increased in Ins2 (96Y/Y) insulinoma cells. In these cells, ER stress was intrinsically induced by mutant insulin expression. The WFS1 gene promoter-luciferase reporter system revealed that the human WFS1 promoter was activated by chemically induced ER stress in MIN6 cells, and that the promoter was more active in Ins2 (96Y/Y) cells than Ins2 (wild/wild) cells.
Wfs1 expression, which is localized to beta- and delta-cells in pancreatic islets, increases in response to ER stress, suggesting a functional link between Wfs1 and ER stress.
European Journal of Endocrinology 08/2005; 153(1):167-76. · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Huntingtin-associated protein 1 (HAP1) was identified as an interactor of the gene product (Huntingtin) responsible for Huntington's disease and found to be a core component of the stigmoid body. Even though HAP1 is highly expressed in the brain, detailed information on HAP1 distribution has not been fully described. Focusing on the neuroanatomical analysis of HAP1-mRNA expression using in situ hybridization histochemistry, the present study clarified its detailed regional distribution in the entire mouse brain. Mouse HAP1 (Hap1)-mRNAs were abundantly expressed in the limbic-related forebrain regions and midline/periventricular brainstem regions including the olfactory bulb, limbic-associated cortices, hippocampus, septum, amygdala, bed nucleus of the stria terminalis, preoptico-hypothalamic regions, central gray, raphe nuclei, locus coeruleus, parabrachial nuclei, nucleus of the solitary tract, and area postrema. In contrast, little expression was detected in the striatum and thalamus, implying that Hap1 is associated with neurodegeneration-sparing regions rather than target lesions in Huntington's disease. The distribution pattern, resembling that of the stigmoid body, suggests that HAP1 and the stigmoid body are implicated in protection from neuronal death rather than induction of neurodegeneration in Huntington's disease, and that they play an important role in integrating instinct behaviors and underlying autonomic, visceral, arousal, drive, memory, and neuroendocrinergic functions, particularly during extensive homeostatic or emotional processes. These data will provide an important morphological base for a future understanding of functions of HAP1 and the stigmoid body in the brain.
The Journal of Comparative Neurology 11/2004; 478(1):88-109. · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sex steroids have been inferred to be involved in the regulation of affective status at least partly through the serotonergic (5-HT) system, particularly in the dorsal raphe nucleus (DRN), which innervates enormous projections to the cerebral cortex and limbic system. In the present study, the expression of estrogen receptors-alpha and -beta (ERalpha, ERbeta), androgen receptor (AR) and 5-HT was examined immunohistochemically in the rat and mouse DRN in both sexes. The results showed that large numbers of ERalpha- and/or ERbeta-immunoreactive (ERalpha-I, ERbeta-I) cells were found in the DRN of both male and female mice, whereas only small numbers of ERalpha-I cells and no ERbeta-I cells were seen in the rat DRN of each sex. With respect to AR-immunoreactive (AR-I) cells, moderate numbers of such cells were present only in male rats and mice, and no or very few could be observed in female ones. The ERalpha-I, ERbeta-I, and AR-I cells were mainly distributed in the rostral DRN. In double-immunostaining, many 5-HT-I neurons were found to show ERalpha and/or ERbeta expression specifically in the rostral DRN (particularly dorsal, ventral and interfascicular parts) of mice of both sexes, but not in that of rats. In contrast, only a few 5-HT neurons were observed to show AR expression in the DRN of both rodents. The current results strongly suggest that sex steroids can modulate the affective regulation of the serotonergic system through ERalpha and/or ERbeta in 5-HT neurons of the mouse rostral DRN (but not so much through AR), and that such effects might be different depending on the sex and species, as shown by the prominent sex differences in AR expression and prominent species differences in ERalpha and ERbeta expression.
Neuroscience Research 07/2004; 49(2):185-96. · 2.20 Impact Factor