Abstract
We have previously shown that early growth response (Egr) 1-deficient mice exhibit female infertility, reflecting a luteinizing hormone (LH) beta deficiency. Egr-1 activates the LHbeta gene in vitro through synergy with steroidogenic factor-1 (SF-1), a protein required for gonadotrope function. To test if this synergy is essential for gonadotropin-releasing hormone (GnRH) stimulation of LHbeta, we examined the activity of the LHbeta promoter in the gonadotrope cell line LbetaT2. GnRH markedly stimulated the LHbeta promoter (15-fold). Mutation of either Egr-1 or SF-1 elements within the LHbeta promoter attenuated this stimulation, whereas mutation of both promoter elements abrogated GnRH induction of the LHbeta promoter. Furthermore, GnRH stimulated Egr-1 but not SF-1 expression in LbetaT2 cells. Importantly, overexpression of Egr-1 alone was sufficient to enhance LHbeta expression. Although other Egr proteins are expressed in LbetaT2 cells and are capable of interacting with SF-1, GnRH stimulation of Egr-1 was the most robust. We also found that the nuclear receptor DAX-1, a repressor of SF-1 activity, reduced Egr-1-SF-1 synergy and diminished GnRH stimulation of the LHbeta promoter. We conclude that the synergy between Egr-1 and SF-1 is essential for GnRH stimulation of the LHbeta gene and plays a central role in the dynamic regulation of LHbeta expression.
Highlights
Endocrine signals within the female hypothalamus-pituitary-gonad axis regulate ovarian follicle development, ovulation, and steroidogenesis
We found that gonadotropin-releasing hormone (GnRH) enhanced the activity of the luteinizing hormone (LH) reporter in a time- and concentration-dependent fashion, and two GnRH pulses (100 nM each) given for 24 and 8 h resulted in maximum enhancement (15-fold) of the LH reporter gene
steroidogenic factor-1 (SF-1) Ϫ/Ϫ mice are deficient in LH production [33, 38], which can be restored with GnRH administration [33]
Summary
GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; Egr, early growth response; SF-1, steroidogenic factor-1; DAX-1, dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on chromosome X, gene 1; PCR, polymerase chain reaction; CMV, cytomegalovirus. Whereas diverse signaling pathways converge on the modulation of LH gene expression (4, 8 –15), recent analysis of mice bearing loss of function mutations in either early growth response-1 (Egr-1, known as NGFI-A, Zif268, or Krox24) or steroidogenic factor-1 (SF-1) demonstrated that these two transcription factors play a critical role in directing LH expression (16 –19). Several studies [12, 38] indicated that SF-1 is absolutely required for LH expression, subsequent analysis of SF-1 Ϫ/Ϫ mice, maintained until maturity by corticosteroid rescue treatment, revealed that these. We and others [16, 29] have recently demonstrated that a synergistic interaction between Egr-1 and SF-1 is essential for the activation of the LH promoter in vitro, suggesting that SF-1 and Egr-1 may provide a means of directing LH expression in response to physiological stimuli that orchestrate gonadotrope function. We tested our hypothesis utilizing the gonadotrope cell line LT2, which expresses Egr-1 and SF-1 and responds to GnRH administration with LH production (40 – 42)
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