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      Cloning, Distribution, and Colocalization of MNAR/PELP1 with Glucocorticoid Receptors in Primate and Nonprimate Brain

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          Abstract

          MNAR/PELP1 (see text) is a newly identified scaffold protein/coactivator initially thought to modulate nongenomic and genomic actions of the estrogen receptor; however, it has been recently shown to interact with multiple steroid receptors, including androgen and glucocorticoid receptors. In the present study, we cloned the monkey MNAR/PELP1 gene, deduced its domain structure, examined its localization pattern and colocalization with glucocorticoid receptor in monkey brain, and determined its subcellular localization. PCR-based cloning of MNAR/PELP1 from monkey brain produced a transcript of ∼3.4 kb which showed high homology to the human and rat MNAR/PELP1 gene. Domain analysis showed that all the key steroid-receptor-interacting (LXXLL) domains, SH3-interacting (PXXP) domains and several C-terminal glutamic-acid-rich clusters, as well as various kinase domains are conserved in the monkey MNAR/PELP1 gene. Anatomical mapping of MNAR/PELP1 immunoreactivity in several regions of the monkey brain showed a similar pattern of MNAR/PELP1 distribution as previously observed in rat and mouse brains. MNAR/PELP1 also showed an absolute colocalization with glucocorticoid receptors in both primate and nonprimate brain, including those regions of the brain, where other steroid receptors are not significantly expressed, such as hippocampus, striatum, and thalamus – suggesting that MNAR/PELP1 may modulate glucocorticoid actions in the brain. Finally, ultrastructural electron microscopic studies showed that MNAR/PELP1-reactive gold particles are located within nucleus, cytoplasm, dendritic/synaptic terminals, and astrocytic processes. As a whole, the studies demonstrate that MNAR/PELP1 is expressed and colocalizes with glucocorticoid receptors in monkey and rat brains and may have multiple cellular functions based on its subcellular localizations.

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          Most cited references 20

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          Control of dendritic arborization by the phosphoinositide-3'-kinase-Akt-mammalian target of rapamycin pathway.

          The molecular mechanisms that determine the size and complexity of the neuronal dendritic tree are unclear. Here, we show that the phosphoinositide-3' kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway promotes the growth and branching of dendrites in cultured hippocampal neurons. Constitutively active mutants of Ras, PI3K, and Akt, or RNA interference (RNAi) knockdown of lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome Ten), induced growth and elaboration of dendrites that was blocked by mTOR inhibitor rapamycin and/or by overexpression of eIF-4E binding protein 1 (4E-BP1), which inhibits translation of 5' capped mRNAs. The effect of PI3K on dendrites was lost in more mature neurons (>14 d in vitro). Dendritic complexity was reduced by inhibition of PI3K and by RNAi knockdown of mTOR or p70 ribosomal S6 kinase (p70S6K, an effector of mTOR). A rapamycin-resistant mutant of mTOR "rescued" the morphogenetic effects of PI3K in the presence of rapamycin. By regulating global and/or local protein translation, and as a convergence point for multiple signaling pathways, mTOR could play a central role in the control of dendrite growth and branching during development and in response to activity.
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            Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation.

            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. (c) 2005 Wiley-Liss, Inc.
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              Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites.

              Estrogen may mediate some of its effects on hippocampal function through the alpha isoform of the estrogen receptor (ERalpha). By light microscopy, ERalpha-immunoreactivity (-I) is found in the nuclei of scattered inhibitory gamma-aminobutyric acid (GABA)ergic interneurons. However, several lines of evidence indicate that estrogen also may exert some of its effects through rapid nongenomic mechanisms, possibly by binding to plasma membranes. Thus, to determine whether ERalpha is found in extranuclear sites in the hippocampal formation (HF), four different antibodies to ERalpha were localized by immunoelectron microscopy in proestrous rats. Ultrastructural analysis revealed that in addition to interneuronal nuclei, ERalpha-I was affiliated with the cytoplasmic plasmalemma of select interneurons and with endosomes of a subset of principal (pyramidal and granule) cells. Moreover, ERalpha labeling was found in profiles dispersed throughout the HF, but slightly more numerous in CA1 stratum radiatum. Approximately 50% of the ERalpha-labeled profiles were unmyelinated axons and axon terminals that contained numerous small, synaptic vesicles. ERalpha-labeled terminals formed both asymmetric and symmetric synapses on dendritic shafts and spines, suggesting that ERalphas arise from sources in addition to inhibitory interneurons. About 25% of the ERalpha-I was found in dendritic spines, many originating from principal cells. Within spines, ERalpha-I often was associated with spine apparati and/or polyribosomes, suggesting that estrogen might act locally through the ERalpha to influence calcium availability, protein translation, or synaptic growth. The remaining 25% of ERalpha-labeled profiles were astrocytes, often located near the spines of principal cells. Collectively, these results suggest that ERalpha may serve as both a genomic and nongenomic transducer of estrogen action in the HF. Copyright 2000 Wiley-Liss, Inc.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2006
                March 2007
                28 March 2007
                : 84
                : 5
                : 317-329
                Affiliations
                aInstitute of Molecular Medicine and Genetics, bInstitute of Neuroscience, cDepartment of Pharmacology and Toxicology and Alzheimer’s Research Center, dDepartment of Cell Biology and Anatomy, School of Medicine, Medical College of Georgia, and eDepartment of Veterans Affairs Medical Center, Augusta Ga., USA
                Article
                97746 Neuroendocrinology 2006;84:317–329
                10.1159/000097746
                17142998
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 6, References: 26, Pages: 13
                Categories
                CRF, Adrenocorticotropin, Adrenal Steroids and Stress

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