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Submitted on April 2, 2003
Accepted on December 23, 2003
Gene Expression in an Activin-Dependent Manner in Immortalized Gonadotropes
1 Departments of Reproductive Medicine and Neurosciences, Center for the Study of Reproductive Biology and Disease, University of California, San Diego, La Jolla, California 92093-0674
* To whom correspondence should be addressed. E-mail: pmellon{at}ucsd.edu.
Little is known about the molecular mechanisms of androgen regulation of the FSH
gene; however, studies suggest that it consists of a complex feedback loop that involves multiple mechanisms acting at both the level of the hypothalamus and the pituitary. In the present study, we address androgen regulation of the FSH
gene in immortalized gonadotrope cells and investigate the roles of activin and GnRH (GnRH) in androgen action. Using transient transfection assays in the FSH
-expressing mouse gonadotrope cell line, L
T2, we demonstrate that androgens stimulate expression of an ovine FSH
reporter gene in a dose-dependent manner. Mutation of either of two conserved androgen response elements at -245/-231 and -153/-139 within the proximal region of the ovine FSH
gene promoter abolishes this stimulation and androgen receptor binds directly to the -244 ARE in vitro. Androgen induction of the FSH
reporter gene is also dependent upon the activin autocrine loop present in the L
T2 cells, as well as an activin-response element at -138/-124 of the FSH
gene. However, activin regulation of other genes remains unaffected by androgens. In addition, androgens stimulate expression of a mouse GnRH receptor reporter gene, and thus may indirectly augment the response of the FSH
gene to GnRH. Taken together, these data demonstrate that, in mouse gonadotropes, androgens act directly on the ovine FSH
gene to stimulate expression by a mechanism that is dependent upon activin, as well as acting indirectly, potentially through a second mechanism that may be dependent upon induction of GnRH receptor.
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