Estrogen - Reelin cross talk im Ovar und im Hippocampus
Zusammenfassung der Projektergebnisse
In this grant application, we raised the question whether expression of reelin, an extracellular matrix protein, which plays essential roles during development and in synaptogenesis, and aromatase expression, the final enzyme in estrogen synthesis and an important player in synaptogenesis, interact with each other. We had previously shown that reelin expression is estrogen-responsive in the hippocampus. Strong expression of estrogen receptor alpha was found in Cajal-Retzius (CR) cells, which synthesize and secrete reelin. In hippocampal slice cultures, application of estradiol causes an increase in reelin expression in CR cells, which is abolished after blockade of estrogen receptors. Vice versa, inhibition of aromatase activity in hippocampal slice cultures by letrozole results in reduced reelin expression, suggesting that local estradiol synthesis in the hippocampus affects reelin expression. Our hypothesis was furthermore substantiated by our finding that in reelin deficient "reeler" mice aromatase was downregulated together with consistent alterations in estrogen receptor expression. As a first step, we used ovaries as a model system, since ovaries express reelin and are a major source of estradiol. We found that in wild-type mice, reelin and aromatase are expressed in granulosa cells of growing follicles. The expression of reelin varies with the estrus cycle and is highest shortly before ovulation, when estradiol serum levels are at their maximum. In ovaries of reelin-deficient reeler mice, aromatase mRNA and protein are significantly reduced in granulosa cells of preovulatory follicles. In line with reduced estradiol synthesis, ovarian estrus cycle length is prolonged in reeler mice. Most importantly, treating cultured granulosa cells with recombinant reelin results in significant upregulation of aromatase mRNA and protein and increased secretion of estradiol into the supernatant. Hence, these data show that not only aromatase expression/estradiol controls reelin but also reelin regulates aromatase activity and estradiol synthesis. Regarding reproduction, this crosstalk may contribute to follicular stability and counteract luteinization in ovaries. Despite of clearly reduced aromatase expression in the hippocampus of reeler mice, we failed to demonstrate the crosstalk between reelin and aromatase, which was clearly evident in ovaries, in the hippocampus. We are convinced that the very small amounts of estradiol, which were frequently under the detection limit of our assays, account for this failure. Upon reduced aromatase expression in the hippocampus we also re-evaluated synapse density in the hippocampus of reeler mice. It was shown that dendritic spine density was clearly reduced in reeler and we speculated whether this spine loss might be rescued by treatment of reeler with estradiol. It came as a big surprise that we did not find any effect on spine synapse density, neither at very young nor at more advanced ages and neither in female nor in male mutants. Vice versa, we also did not find any migratory deficits, which are typical for reeler mice, in aromatase deficient mice. Finally, we tested whether estradiol regulates the compartmentalization of HCN1 in CA1 via Reelin, which was previously proposed to be regulated directly by Reelin. The HCN1 compartmentalization is essential for hippocampal information processing. We found that distal dendritic enrichment of HCN1 channels in hippocampal CA1 is promoted by estrogen but does not require reelin.
Projektbezogene Publikationen (Auswahl)
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(2018) Reelin and aromatase cooperate in ovarian follicle development. Scientific reports 8 (1) 8722
Meseke, Maurice; Pröls, Felicitas; Schmahl, Camilla; Seebo, Katja; Kruse, Claas; Brandt, Nicola; Fester, Lars; Zhou, Lepu; Bender, Roland; Rune, Gabriele M.
