The molecular mechanism underlying the gonadotropin releasing hormone pulse sensitivity of the follicle stimulating hormone beta subunit gene
- Author(s): Mistry, Devendra S.
- et al.
Gonadotropin synthesis and release is dependent upon pulsatile stimulation by the hypothalamic neuropeptide GnRH. Generally, slow GnRH pulses promote FSH production while rapid pulses favor LH, but the molecular mechanism underlying this pulse sensitivity is poorly understood. In this study, we develop and test a model for FSH[beta] regulation in mouse L[beta]T2 gonadotropes. We observed that positive regulators of FSH[beta] expression, such as c-fos and c-jun, were upregulated at slower pulse frequencies than a number of potential negative regulators, such as the co-repressors SnoN, CREM and TGIF1. These latter co-repressors reduced FSH[beta] promoter activity whether driven by transfection of individual transcription factors or by treatment with GnRH and activin. Overexpression of Smad binding or phosphorylation defective SnoN and TGIF mutants, however, failed to repress FSH[beta] promoter activity. Knock down of the endogenous repressors SnoN and TGIF, but not CREM, increased FSH[beta] promoter activity driven by continuous GnRH or activin. ChIP analysis showed that c-fos, SnoN and TGIF1, and to a lesser degree c-jun, occupy the FSH[beta] promoter in a cyclical manner following GnRH stimulation. Overexpression of corepressors SnoN or TGIF repressed induction of the FSH[beta] promoter at the slow GnRH pulse frequency, but had little effect at the fast pulse frequency. In contrast, knock down of endogenous SnoN or TGIF selectively increased FSH[beta] mRNA at the fast GnRH pulse frequency. Finally, relative to corepressors, stimulators have greater FSH[beta] promoter occupancy at slow GnRH pulse frequency which favors greater FSH[beta] mRNA production. Therefore, we propose a potential mechanism by which production of gonadotropin FSH[beta] is modulated by positive transcription factors and negative corepressors with different pulse sensitivities