Gonadotropin-Releasing Hormone Pulse Sensitivity of Follicle-Stimulating Hormone beta Gene Is Mediated by Differential Expression of Positive Regulatory Activator Protein 1 Factors and Corepressors SKIL and TGIF1

DEVENDRA MISTRY ; RIE TSUTSUMI; MARINA FERNANDEZ; SHWETA SHARMA ; STEVE CARDENAS; MARK LAWSON; NICHOLAS WEBSTER

MOLECULAR ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2011 vol. 25 p. 1387 - 1403

0888-8809

Gonadotropin synthesis and release is dependent on pulsatile stimulation by the hypothalamic neuropeptide GnRH. Generally, slow GnRH pulses promote FSH production, whereas rapid pulses favor LH, but the molecular mechanism underlying this pulse sensitivity is poorly understood. In this study, we developed and tested a model for FSHbeta regulation in mouse LbetaT2 gonadotropes. By mining a previous microarray data set, we found that mRNA for positive regulators of FSHbeta expression, such as Fos and Jun, were up-regulated at slower pulse frequencies than a number of potential negative regulators, such as the corepressors Skil, Crem, and Tgif1. These latter corepressors reduced FSHbeta promoter activity whether driven by transfection of individual transcription factors or by treatment with GnRH and activin. Overexpression of binding or phosphorylation-defective ski-oncogene-like protein (SKIL) and TG interacting factor (TGIF1) mutants, however, failed to repress FSHbeta promoter activity. Knockdown of the endogenous repressors SKIL and TGIF1, but not cAMP response element-modulator, increased FSHbeta promoter activity driven by constant GnRH or activin. Chromatin immunoprecipitation analysis showed that FOS, SKIL, and TGIF1 occupy the FSHbeta promoter in a cyclical manner after GnRH stimulation. Overexpression of corepressors SKIL or TGIF1 repressed induction of the FSHbeta promoter at the slow GnRH pulse frequency but had little effect at the fast pulse frequency. In contrast, knockdown of endogenous SKIL or TGIF1 selectively increased FSHbeta mRNA at the fast GnRH pulse frequency. Therefore, we propose a potential mechanism by which production of gonadotropin FSHbeta is modulated by positive transcription factors and negative corepressors with different pulse sensitivities.