Regulation of gonadotropin gene expression by Müllerian inhibiting substance

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National Academy of Sciences

RESUMO

In addition to its role in causing Müllerian duct regression, Müllerian inhibiting substance (MIS) is implicated in the regulation of steroidogenesis, breast and prostate growth, and ovarian follicle recruitment, all of which are processes controlled or influenced by the hypothalamic–pituitary–gonadal axis. Whereas the direct effect of MIS on gonadal, prostate, and breast cells is under investigation, the ability of MIS to modulate pituitary function, thereby affecting those tissues indirectly, has not yet been studied. Using LβT2 cells, a murine gonadotrope-derived cell line, we have evaluated the effects of MIS on the expression of the gonadotropin genes. We show that both LβT2 cells and adult rat pituitaries express MIS type II receptor (MISRII) mRNA. Within 2 h, follicle-stimulating hormone β subunit (FSHβ) mRNA levels are significantly induced by addition of MIS to LβT2 cells and remain elevated through 8 h of treatment. Transcriptional activation of both the FSHβ and luteinizing hormone β subunit (LHβ) gene promoters was observed by MIS, which enhances the effect of gonadotropin-releasing hormone (GnRH) agonist on the FSHβ gene promoter and synergizes with the GnRH agonist to stimulate LHβ gene promoter activity. Addition of MIS to LβT2 cells stimulates the activity of the rat LHβ gene promoter with as little as 1 μg/ml and in a dose-dependent manner. These studies report both MISRII expression in rat pituitary cells and a gonadotrope-derived cell line and MIS-mediated activation of LHβ and FSHβ gene expression, and suggest that MIS may modulate the hypothalamic–pituitary–gonadal axis at more than one level.

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