Estrogen receptor alpha (ER alpha) and ER beta are members of the steroid nuclear receptor family that modulate gene transcription in an estrogen-dependent manner. ER mRNA and protein have been detected both peripherally and in the central nervous system, with most data having come from the rat. Here we report the development of an ER beta-selective antibody that cross-reacts with mouse, rat, and human ER beta protein and its use to determine the distribution of ER beta in the murine brain. Further, a previously characterized polyclonal antibody to ER alpha was used to compare the distribution of the two receptors in the first comprehensive description of ER distribution specifically in the mouse brain. ER beta immunoreactivity (ir) was primarily localized to cell nuclei within select regions of the brain, including the olfactory bulb, cerebral cortex, septum, preoptic area, bed nucleus of the stria terminalis, amygdala, paraventricular hypothalamic nucleus, thalamus, ventral tegmental area, substantia nigra, dorsal raphe, locus coeruleus, and cerebellum. Extranuclear-ir was detected in several areas, including fibers of the olfactory bulb, CA3 stratum lucidum, and CA1 stratum radiatum of the hippocampus and cerebellum. Although both receptors were generally expressed in a similar distribution through the brain, nuclear ER alpha-ir was the predominant subtype in the hippocampus, preoptic area, and most of the hypothalamus, whereas it was sparse or absent from the cerebral cortex and cerebellum. Collectively, these findings demonstrate the region-selective expression of ER beta and ER alpha in the adult ovariectomized mouse brain. These data provide an anatomical framework for understanding the mechanisms by which estrogen regulates specific neural systems in the mouse.
______________________________________________________________________Development of new therapeutics for chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), which pose a huge public health burden 1 , have been hindered by the inability to study organ-level complexities of lung inflammation in vitro. While hospitalization and mortality due to these diseases are often the consequences of exacerbations triggered by pathogens 2, 3 , there is currently no way to study these processes in human lung outside of the clinical setting. Animal models of asthma and COPD exist; however, their clinical relevance is questionable because the anatomy, immune system and inflammatory responses exhibited by animal lungs differ greatly from those in humans [4][5][6] . For example, mucin-producing cells, which are central to the development of asthma, are less frequent in the respiratory tree of mice and rats compared with humans 6 . Neutrophils that increase dramatically in the lungs of patients with COPD and severe asthma 7-9 also comprise only 10-25% of circulating leukocytes in mice, whereas they represent 50-70% in humans 5 . Because many animal models fail to predict drug activities in humans, the pharmaceutical and biotechnology industries strive to reduce or replace animal models for drug testing whenever possible 10 .Airway inflammatory diseases have been modeled in vitro using cultures of primary or immortalized human epithelial cells, sometimes positioned at an air-liquid interface to induce epithelial differentiation 11 or using co-cultures of airway epithelium and tissue-resident immune cells (e.g., macrophages or dendritic cells) 12 . However, lung inflammation is mediated by organ-level responses that involve complex tissuetissue interactions between the lung airway epithelium and underlying microvascular endothelium that modulate immune reactions to respiratory pathogens and allergens [13][14][15] and alter the vascular cell adhesion molecular machinery that recruits circulating immune cells, such as neutrophils. This is important because neutrophil accumulation in the lung is associated with enhanced severity of airflow limitation in COPD patients 7 and it plays a critical role in severe asthma as well 8 . Unfortunately, it is not possible to study complex interactions among airway epithelium, endothelium and circulating neutrophils using existing in vitro lung models because most fail to recapitulate normal functional coupling between the epithelium and endothelium, and none enable analysis of recruitment of circulating immune cells under active fluid flow. This latter point is crucial because neutrophil adhesion to inflamed endothelium involves initial rolling along the luminal surface of endothelium mediated by E-selectin, which is then followed by firm adhesion to and this dynamic shear stress-dependent response cannot be studied in a physiologically relevant way using static cell cultures.Advances in microsystems engineering have recently made it possible to create bio...
Several lines of evidence indicate that estrogen affects hippocampal synaptic plasticity through rapid nongenomic mechanisms, possibly by binding to plasma membrane estrogen receptors (ERs). We have previously shown that ERalpha immunoreactivity (ir) is in select interneuron nuclei and in several extranuclear locations, including dendritic spines and axon terminals, within the rat hippocampal formation (Milner et al., [2001] J Comp Neurol 429:355). The present study sought to determine the cellular and subcellular locations of ERbeta-ir. Coronal hippocampal sections from diestrus rats were immunolabeled with antibodies to ERbeta and examined by light and electron microscopy. By light microscopy, ERbeta-ir was primarily in the perikarya and proximal dendrites of pyramidal and granule cells. ERbeta-ir was also in a few nonprincipal cells and scattered nuclei in the ventral subiculum and CA3 region. Ultrastructural analysis revealed ERbeta-ir at several extranuclear sites in all hippocampal subregions. ERbeta-ir was affiliated with cytoplasmic organelles, especially endomembranes and mitochondria, and with plasma membranes primarily of principal cell perikarya and proximal dendrites. ERbeta-ir was in dendritic spines, many arising from pyramidal and granule cell dendrites. In both dendritic shafts and spines, ERbeta-ir was near the perisynaptic zone adjacent to synapses formed by unlabeled terminals. ERbeta-ir was in preterminal axons and axon terminals, associated with clusters of small, synaptic vesicles. ERbeta-labeled terminals formed both asymmetric and symmetric synapses with dendrites. ERbeta-ir also was detected in glial profiles. The cellular and subcellular localization of ERbeta-ir was generally similar to that of ERalpha, except that ERbeta was more extensively found at extranuclear sites. These results suggest that ERbeta may serve primarily as a nongenomic transducer of estrogen actions in the hippocampal formation.
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