Estrogens derived from the aromatization of androgens are believed to be responsible for the induction of the sexual differentiation of the CNS interacting with specific estrogen receptors (ER) present in developing neurons . However, the brain cellular distribution of ER is not so well documented . The aim of this study was to investigate the qualitative and quantitative expression of ER mRNA in well characterized cultures of rat type 1 and type 2 astrocytes and of oligodendrocytes by polymerase chain reaction . A series of amplifications with a set of primers spanning along the entire ER mRNA was utilized in the different types of glial cells, in a positive control (uterus), and in a negative control (SK-N-BE cell line) previously shown to be devoid of ER . The data obtained show that ER mRNA is expressed in all three types of glial cell analyzed in almost equal amounts, which are 25-50 times lower than those in the uterus . The mRNA expressed in the glia is homologous with that expressed in the uterine tissue .

Several reports demonstrate estrogen receptor involvement in specific brain functions. In addition, estrogen receptors are expressed at early stages of brain development, suggesting that estrogens or related molecules may play an instructive role in the differentiation of specific brain areas. The lack of model systems in which these phenomena could be studied prompted us to develop a neuroblastoma cell line expressing the estrogen receptor. The cell line expresses the hormone receptor at levels compatible with a physiological activity. The activated estrogen receptor is capable of blocking proliferation of the cells without exerting toxic effects. Following growth arrest, the cells display a neuron-like morphology and express T and synaptophysin, two proteins synthesized in differentiating neurons. The cell line generated will provide a valuable model system for molecular and biochemical studies of the activity of estrogens in neural-derived cells.Estrogens are important for regulation of cell growth and maturation of several tissues (e.g., uterus, liver, and brain).

The neuroblastoma cell line SK-ER3, which is stably transfected with the estrogen receptor (ER), was used to study the effect of insulin and insulin-like growth factors (IGF-I and IGF-II) on growth and morphological differentiation induced by estrogens. The data demonstrate that insulin and related growth factors control the growth and morphological differentiation of the cell line expressing the ER, but not of the parental cell line. Effects elicited by the growth factors in SK-ER3 cells can be blocked by ER antagonists. Transient transfection studies further confirm an effect of the IGFs in modulation of ER-activated promoters. The results presented support the hypothesis of the existence of cross-talk between membrane and intracellular receptors and provide evidence for physiological consequences of the activation of such a pathway of communication. The present study is of particular interest with regard to the theory of prenatal involvement of the ER in maturation of nerve cells. It could, in fact, be hypothesized that IGF-I and IGF-II, present in high concentrations in the developing brain, might activate the ER expressed in several embryonic brain nuclei.

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Antisense oligos complementary to the 5-end, but not to the 3-end, of the estrogen receptor (ER) messenger RNA caused a paradox accumulation of ER protein in MCF-7 cells. The same effect was observed after treatment of the cells with the corresponding sense oligos. The oligos interfering with ER down-regulation were demonstrated to specifically bind the ER with affinities in the nanomolar range. It is, therefore, proposed that the ER up-regulation induced by the oligos might be due to squelching of the ER (or ER-inducible proteins) from their binding site located in the 5-end of the ER gene. We also report that transcriptionally inactive ER mutants can undergo down-regulation, and that in denaturing gels, the migration profile of ER-oligo and ER-estrogen-responsive element complexes are dissimilar. We, therefore, propose that ER can interact with DNA in different ways and at different binding sites. These observations might have important pharmacological consequences, since specific drugs could be devised to induce the ER conformation necessary to perform only selected tasks of the ER transcriptional repertoire. (Molecular Endocrinology 11: 938-949, 1997)