Abstract
Reelin plays an important role in cerebral cortex development and synaptogenesis. In the hippocampus, the neurosteroid estrogen affects reelin expression. In this study we tested a potential crosstalk between estradiol and reelin, thus the possibility of a reelin-induced activation of the estradiol synthesizing enzyme aromatase. As a model system, we used ovaries, which 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, as evidenced by real-time PCR, western blot analysis, and quantitative immunohistochemistry 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. Our data provide evidence of a local increase of aromatase expression by reelin. Regarding reproduction, this crosstalk may contribute to follicular stability and counteract luteinization in ovaries.
Highlights
Reelin is an extracellular matrix protein (ECM), and it has frequently been demonstrated that it is essential for cortical development
Using real time PCR, reelin expression in the ovaries and in the cerebral cortex of the same mouse were quantified; this showed that the amount of reelin mRNA is more than 5 times lower in the ovaries than in cortex, yet substantial expression of reelin mRNA in mice ovaries is clearly evident (Fig. 1c)
Since ovarian cyclicity is widely reflected by cyclic estradiol synthesis, and aromatase is downregulated in the ovaries of reeler mice, we studied the length of the estrus cycle in reeler mice by inspecting vaginal swabs
Summary
Reelin is an extracellular matrix protein (ECM), and it has frequently been demonstrated that it is essential for cortical development. Migratory deficits of GnRH neurons in reeler mice may result in altered levels of gonadal steroid hormone secretion in ovaries of reeler mice. In turn, eventually may contribute to the impaired fertility in reeler mice, which was shown by Caviness et al, and Goffinet[17,18]. Another possibility, could be that reelin, and aromatase, the final enzyme in estrogen synthesis, regulate each other. To address this question of a direct crosstalk between reelin and aromatase we used ovaries and granulosa cell cultures, which have been shown to express reelin[20,21] and which are a major source of estradiol. The female gonads, and in particular granulosa cells, appear to be suitable for investigating a potential crosstalk between aromatase and reelin
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