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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online January 22, 2003 as doi:10.1096/fj.02-0513fje. |
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Gender Health Care Research, Schering AG/Jenapharm, 07745 Jena, Germany; and
* Department of Neuroendocrinology, Max Planck Institute of Psychiatry, 80804 Munich, Germany
2Correspondence: Jenapharm GmbH & Co. KG, Otto-Schott-St. 15, 07745 Jena, Germany. E-mail: Vladimir.Patchev{at}jenapharm.de
SPECIFIC AIM
The steroid receptor coactivator-1 (SRC-1) acts as an "amplifier" of transcription mediated by nuclear receptors in several organs and has distinct regional expression in the brain. To date, neither the significance of this coactivator for the region-specific efficacy of estrogen signaling in the adult brain nor its ontogeny and regulation by estrogens in specific brain sites have been examined. This study describes the expression profile of SRC-1 throughout postnatal development and the influence of changes in circulating estrogen levels on SRC-1 mRNA expression in estrogen-responsive regions of the female rat brain.
PRINCIPAL FINDINGS
1. Developmental profiles of SRC-1 expression in the brain display regional differences
Comparison between different developmental ages (newborn, 7 days, puberty, and sexual maturity) revealed striking differences in the regional abundance of SRC-1-encoding transcripts. In the cerebral cortex, SRC-1 mRNA levels gradually decreased with increasing age; in the adult brain, specific signal intensity was 
30% of that measured in neonates. Two estrogen-sensitive brain areas involved in the control of gonadal hormone secretion and sexual behavior—the medial preoptic area (MPOA) and hypothalamic ventromedial nucleus (VMN)—displayed low SRC-1 transcript densities at birth, with transient peak of expression occurring at puberty (Fig. 1
).
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2. Differential region-specific responsiveness of SRC-1 expression to changes in estrogen levels in the adult brain
In the VMN of intact rats, SRC-1 mRNA levels showed ovarian cycle-associated and estrogen treatment-induced changes. A significant increase in SRC-1 mRNA expression was measured at proestrus compared with diestrus; gonadectomy resulted in markedly decreased SRC-1 transcript densities, whereas estradiol substitution in ovariectomized rats up-regulated SRC-1 mRNA levels in the VMN. Expression of SRC-1 in the cerebral cortex was neither influenced by cyclic changes in ovarian steroid secretion nor displayed significant changes on alterations of circulating estrogen levels by ovariectomy and estradiol substitution (Fig. 2
).
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CONCLUSIONS AND SIGNIFICANCE
The steroid receptor coactivator-1 protein (SRC-1/NcoA-1) has been demonstrated to be a significant amplifier of estrogen receptor-mediated signaling. Given the important role of estradiol in determining the circuitry and responsive potential of estrogen-sensitive brain areas throughout life, postnatal ontogenetic spatio-temporal mapping, and examination of region-specific influences of estrogens on SRC-1 expression provide insight into the role of this molecule as a modifier of estradiol signaling efficacy in specific brain areas during development and in adulthood. SRC-1 is abundantly expressed in several brain areas with distinct functional specialization, such as cognitive processing (cortex) and reproductive hormone secretion and behavior (MPOA, VMN). In summary, our findings indicate that 1) SRC-1 expression in the rat brain displays region-specific developmental profiles; 2) the temporal changes in SRC-1 expression differ markedly between brain regions involved in cognitive functions vs. those concerned with the neural control of reproductive hormone secretion and behavior, and 3) in the adult female rat brain, circulating levels of estrogens influence SRC-1 gene transcription in neuronal populations "specialized" in the regulation of the neural control of reproduction.
These observations suggest that in the developing brain, SRC-1 may be required for "amplification" of estrogen-mediated growth of dendrites and establishment of synaptic connections in cortical neurons; in the adult cortex, the relative paucity of SRC-1 expression and its refractoriness to regulation by estrogen suggest that this coactivator is unlikely to play a major role in the cognitive-enhancing effects attributed to estrogen.
The developmental expression profiles and responsiveness to estrogens of SRC-1 in the VMN and MPOA, two brain areas of crucial significance in the neuroendocrine regulation of the gonadal axis and reproductive behavior, strongly suggest that SRC-1 is a key player in "assigning" unique thresholds of discrimination with respect to estrogen signaling. At least in specific areas such as the VMN and MPOA, physiological or pharmacologically-induced increases in estrogen levels result in selective stimulation of SRC-1 transcription; this indicates cooperativity between the ER ligand and its transcriptional signal amplifier. This mutual stimulatory action is ultimately manifested as a coordinated secretory signal (gonadotropin surge) and induction of sexual behavior (Fig. 3
).
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The coactivator SRC-1 may be instrumental in assigning high estrogen responsiveness to reproduction-relevant neuronal populations during brain development and amplification of estrogen receptor-dependent transcription in a temporally and spatially coordinated manner in these structures in adulthood.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0513fje; to cite this article, use FASEB J. (January 22, 2003) 10.1096/fj.02-0513fje 
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