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Distribution and Corticosteroid Regulation of Glucocorticoid Receptor in the Brain of Xenopus Laevis

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Distribution and Corticosteroid Regulation of Glucocorticoid Receptor in the Brain of Xenopus Laevis THE JOURNAL OF COMPARATIVE NEUROLOGY 508:967–982 (2008) Distribution and Corticosteroid Regulation of Glucocorticoid Receptor in the Brain of Xenopus laevis MENG YAO, FANG HU, AND ROBERT J. DENVER* Department of Molecular, Cellular and Developmental Biology, The University of Michigan, Ann Arbor, Michigan 48109-1048 ABSTRACT Glucocorticoids (GCs) play essential roles in physiology, development, and behavior that are mediated largely by the glucocorticoid receptor (GR). Although the GR has been inten- sively studied in mammals, very little is known about the GR in nonmammalian tetrapods. We analyzed the distribution and GC regulation of GR in the brain of the frog Xenopus laevis by immunohistochemistry. GR-immunoreactive (GR-ir) cells were widely distributed, with the highest densities in the medial pallium (mp; homolog of the mammalian hippocampus), accumbens, anterior preoptic area (POA; homolog of the mammalian paraventricular nu- cleus), Purkinje cell layer of the cerebellum, and rostral anterior pituitary gland (location of corticotropes). Lower but distinct GR-ir was observed in the internal granule cell layer of the olfactory bulbs, dorsal and lateral pallium, striatum, various subfields of the amygdala, bed nucleus of the stria terminalis (BNST), optic tectum, various tegmental nuclei, locus coer- uleus, raphe nuclei, reticular nuclei, and the nuclei of the trigeminal motor nerves. Treat- ment with corticosterone (CORT) for 4 days significantly decreased GR-ir in the POA, mp, medial amygdala (MeA), BNST, and rostral pars distalis. Treatment with the corticosteroid synthesis inhibitor metyrapone (MTP) also significantly reduced GR-ir in the POA, mp, MeA and BNST, but not in the rostral pars distalis. Replacement with a low dose of CORT in MTP-treated animals reversed these effects in brain. Thus, chronic increase or decrease in circulating corticosteroids reduces GR-ir in regions of the frog brain. Our results show that the central distribution of GR-ir and regulation by corticosteroids are highly conserved among vertebrates. J. Comp. Neurol. 508:967–982, 2008. © 2008 Wiley-Liss, Inc. Indexing terms: glucocorticoid receptor; Xenopus; stress response; hypothalamus; limbic system; hippocampus; amygdala; pituitary Glucocorticoids (GCs) exert diverse developmental, mammals based on their differential binding affinities: physiological, and behavioral actions in vertebrates the high-affinity type I receptor (also called the “mineralo- (Chrousos, 1998; Chrousos and Gold, 1992). The produc- corticoid receptor”; MR; NR3C2) and the lower-affinity tion of GCs by cells of the adrenal cortex (interrenal type II receptor (also called the “glucocorticoid receptor”; glands in nonmammalian species) is controlled by pitu- GR; NR3C1). The GR and MR belong to the nuclear hor- itary adrenocorticotropic hormone (ACTH), whose synthe- mone receptor superfamily, and phylogenetic analysis sis and secretion is controlled by hypothalamic suggests that these two receptors arose by a gene dupli- corticotropin-releasing factor (CRF) and arginine vaso- pressin (AVP). Circulating GC concentration increases rapidly following exposure to stressors, which serves to Grant sponsor: National Science Foundation; Grant number: IBN coordinate physiological and behavioral adjustments to 0235401 (to R.J.D.). maintain homeostasis. Elevated circulating GC concentra- *Correspondence to: Dr. Robert J. Denver, 3065C Kraus Natural Science tion exerts negative feedback at multiple levels of the Bldg., University of Michigan, Ann Arbor, MI 48109-1048. E-mail: [email protected] hypothalamo-pituitary-adrenal (HPA) axis to prevent con- Received 21 November 2007; Revised 31 January 2008; Accepted 13 tinued activation (Makino et al., 2002a). February 2008 The actions of GCs are mediated by two ligand-activated DOI 10.1002/cne.21716 transcription factors that were originally identified in Published online in Wiley InterScience (www.interscience.wiley.com). © 2008 WILEY-LISS, INC. The Journal of Comparative Neurology 968 M. YAO ET AL. cation event in the gnathastome lineage (Bridgham et al., hippocampal formation, paraventricular nucleus (PVN), 2006; Thornton, 2001). In mammals, the MR is hypothe- medial and central nuclei of the amygdala, granule layer sized to function in the maintenance of basal expression of the cerebellar cortex, and locus coeruleus (Ahima and and the circadian rhythm of circulating GCs, whereas Harlan, 1990; Morimoto et al., 1996). The hippocampus most GC-dependent physiological changes that occur in expresses the highest level of GR in the mammal brain, response to stressors, and feedback regulation by GCs is and GC actions here lead to tonic inhibition of neurose- thought to be mediated by the GR (Bamberger et al., 1996; cretory neurons in the PVN via descending inhibitory De Kloet et al., 1998; Wei et al., 2004). In the absence of projections to down-regulate the activity of the HPA axis ligand, the GR is located in the cytosol associated with (Herman et al., 2005). The PVN neurons also express a heat shock proteins and immunophilins (referred to as the high level of GR and thus are direct targets for circulating “foldosome”; Pratt and Toft, 1997). Ligand binding causes GCs (Makino et al., 2002a). GCs influence cognition via disassociation of the protein complex and translocation of actions on the hippocampus and amygdala (Lupien and GR into the nucleus, where GR regulates transcription of McEwen, 1997; Sapolsky, 2003). its target genes (Kumar and Thompson, 2005). Relatively little is known about the central distribution Full-length or partial cDNA sequences for the GR have of GR in nonmammalian species. To our knowledge, noth- been isolated from nonmammalian species, including ing is known about GR distribution in amphibians or birds (chicken, Kwok et al., 2007; zebra finch Taeniopygia reptiles. Except for one report on GR-like immunoreactiv- guttata, Hodgson et al., 2007), fishes (the rainbow trout ity in the Japanese quail (Kova´cs et al., 1989), studies on Onchorhynchus mykiss, Ducouret et al., 1995; tilapia the central distribution of GR in nonmammalian verte- Oreochromis mossambicus, Tagawa et al., 1997; Japanese brates have been conducted with teleost fishes. In the flounder, Tokuda et al., 1999; fathead minnow Pimephales rainbow trout (Oncorhynchus mykiss), among the brain promelas, Filby and Tyler, 2007), and frog Xenopus laevis, regions where GR-ir was observed, the highest densities Gao et al., 1994), and are highly conserved. These genes were found in the ventral telencephalon, preoptic region, were isolated and named based on their sequence similar- mediobasal hypothalamus, and optic tectum (Teitsma et ity to the mammalian GR (Gao et al., 1994; Thornton, al., 1998). Lower densities of GR were seen in the internal 2001). The primary amino acid sequences of the DNA cell layer of the olfactory bulb and lateral regions of the binding domains of X. laevis and human GR are identical, dorsal telencephalon (Teitsma et al., 1998; see also Car- and the hormone binding domains share 86% similarity. ruth et al., 2000, for a study in kokanee salmon). The The N-terminal domains of frog and mammalian GR pro- generally conserved central distribution of GR in fishes teins are less well conserved, sharing 51% similarity at and mammals suggests that expression and function of the amino acid level (Gao et al., 1994). The X. laevis GR GR in the CNS arose early in vertebrate evolution and (xGR), when expressed in COS cells, was capable of me- may be conserved. diating hormone-dependent transactivation of a GRE- In an effort to understand the evolutionary origins of containing promoter to an extent similar to that of the rat GC targets in the CNS, and the roles of GCs in develop- GR (Gao et al., 1994). These data suggest that the struc- ment, physiology, and behavior in extant species, we an- ture and function of GR are evolutionarily conserved alyzed the distribution of GR-ir and GR regulation by GCs among vertebrate species. in the brain and pituitary gland of the frog X. laevis,an GR receptor protein and mRNA are widely distributed important model organism in endocrinology and develop- in the central nervous system (CNS) of rodents (Ahima mental biology. We found that the pattern of GR-ir distri- and Harlan, 1990; Morimoto et al., 1996). The highest bution in the frog brain and pituitary gland is highly levels of GR immunoreactivity (GR-ir) and mRNA were conserved with mammals and fishes. We provide the first found in the cerebral cortex, olfactory pyramidal layers, detailed map of GR-ir distribution in the CNS of a non- Abbreviations A anterior thalamic nucleus ms medial septum Acc nucleus accumbens nII cranial nerve II BNST bed nucleus of the stria terminalis P posterior thalamic nucleus Cb cerebellum pd pars distalis CeA central amygdala pi pars intermedia dp dorsal pallium pn pars nervosa Hd dorsal habenular nucleus POA preoptic area Hv ventral habenular nucleus Ra raphe nucleus IIIv third ventricle Ri inferior reticular nucleus igl internal granule cell layer Rm nucleus reticularis medius Is nucleus isthmi SC suprachiasmatic nucleus L lateral thalamic nucleus Str striatum LA lateral amygdala Lc locus coeruleus tect optic tectum lp lateral pallium tegm mesencephalic tectum LPv lateral thalamic nucleus Tn tegmental nuclei ls lateral septum TP posterior tuberculum lv lateral ventricle VH ventral hypothalamic nucleus ME median eminence VLs superficial ventral nucleus MeA medial amygdala VM ventromedial thalamic nucleus ml mitral layer Vm nucleus motorius nervi trigemini
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