Pituitary

Gonadotropin-Releasing Hormone Regulates Expression of the DNA Damage Repair Gene, Fanconi anemia A, in Pituitary Gonadotroph Cells

Abstract
Gonadal function is critically dependant on regulated secretion of the gonadotropin hormones from anterior pituitary gonadotroph cells. Gonadotropin biosynthesis and release is triggered by the binding of hypothalamic GnRH to GnRH receptor expressed on the gonadotroph cell surface. The repertoire of regulatory molecules involved in this process are still being defined. We used the mouse LT2 gonadotrope cell-line, which expresses both gonadotropin hormones, as a model to investigate GnRH regulation of gene expression and differential display RT-PCR to identify and isolate hormonally induced changes. This approach identified Fanconi anemia A (FancA), a gene implicated in DNA damage repair, as a differentially expressed transcript. Mutations in FancA account for the majority of cases of Fanconi anemia (FA), a recessively inherited disease identified by congenital defects, bone marrow failure, infertility and cancer susceptibility. We confirmed expression and hormonal regulation of FancA mRNA by quantitative RT-PCR, which showed that GnRH induced a rapid, transient increase in FancA mRNA. FancA protein was also acutely up regulated after GnRH treatment of LT2 cells. In addition, FancA gene expression was confined to mature pituitary gonadotropes and adult mouse pituitary and was not expressed in the immature T3-1 gonadotrope cell-line. Thus, this study extends the expression profile of FancA into a highly specialised endocrine cell, and demonstrates hormonal regulation of expression of the FancA locus. We suggest that this regulatory mechanism may have a crucial role in the GnRH-response mechanism of mature gonadotropes and perhaps the etiology of FA.

Key words: Mechanisms of Hormone Action • Pituitary • Anterior pituitary • Gene regulation • Gonadotropin-releasing hormone

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