LIM Homeodomain Transcription Factor Isl-1 Enhances Follicle Stimulating Hormone-β and Luteinizing Hormone-β Gene Expression and Mediates the Activation of Leptin on Gonadotropin Synthesis

The Lin-11, Isl-1, and Mec-3 (LIM) homeodomain transcription factor Isl-1 has been reported to be involved in pituitary development in the early stages of mouse embryogenesis. Our recent studies have shown that Isl-1 is mainly located in the pituitary gonadotropes throughout pituitary development and persists to adulthood. We still do not know the physiological functions of Isl-1 expression and its related mechanisms in the pituitary gland. The aim of the present study was to examine the hypothesis that Isl-1 is involved in regulating pituitary gonadotropin hormone (FSH/LH) production by activating FSH beta and LH beta gene expressions. We have shown that Isl-1 activates FSH beta and LH beta subunit promoters and endogenous gene transcription in L beta T2 cells. In addition, Isl-1 overexpression significantly increased FSH synthesis and secretion but not LH. The actions of Isl-1 were not observed when the homeodomain or LIM1 domains are mutated. This demonstrates that Isl-1 induction of FSH beta and LH beta is by both direct and indirect binding of Isl-1 to DNA sequences. Furthermore, Isl-1 expressional level was up-regulated in L beta T2 cells after exposure to GnRH, activin, and leptin. However, RNA interference-induced knockdown of Isl-1 significantly reduced the effect of leptin but did not obviously influence the stimulating effects of GnRH and activin on LH and FSH production. In conclusion, the results demonstrate that the LIM-homeodomain transcription factor Isl-1 functions to increase FSH beta/LH beta gene transcription, and mediates the effects of leptin on gonadotropin synthesis. (Endocrinology 151: 4787-4800, 2010)