Frequency-Dependent Regulation of Follicle-Stimulating Hormone β by Pulsatile Gonadotropin-Releasing Hormone Is Mediated by Functional Antagonism of bZIP Transcription Factors

Abstract

Oscillatory synthesis and secretion of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), under the control of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH), is essential for normal reproductive development and fertility. The molecular mechanisms by which various patterns of pulsatile GnRH regulate gonadotrope responsiveness remain poorly understood. In contrast to the ␣ and LH␤ subunit genes, FSH␤ subunit transcription is preferentially stimulated at low rather than high frequencies of pulsatile GnRH. In this study, mutation of a cyclic AMP response element (CRE) within the FSH␤ promoter resulted in the loss of preferential GnRH stimulation at low pulse frequencies. We hypothesized that high GnRH pulse frequencies might stimulate a transcriptional repressor(s) to attenuate the action of CRE binding protein (CREB) and show that inducible cAMP early repressor (ICER) fulfills such a role. ICER was not detected under basal conditions, but pulsatile GnRH stimulated ICER to a greater extent at high than at low pulse frequencies. ICER binds to the FSH␤ CRE site to reduce CREB occupation and abrogates both maximal GnRH stimulation and GnRH pulse frequency-dependent effects on FSH␤ transcription. These data suggest that ICER production antagonizes the stimulatory action of CREB to attenuate FSH␤ transcription at high GnRH pulse frequencies, thereby playing a critical role in regulating cyclic reproductive function.The maintenance of normal reproductive function in all vertebrate species is dependent on the regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and release by pituitary gonadotropes. These hormones are released in a pulsatile manner to regulate gametogenesis and gonadal hormone synthesis (2,11,17). The intermittent synthesis and secretion of LH and FSH by pituitary gonadotropes are tightly regulated, as evidenced by predictable and reproducible changes in circulating levels throughout the menstrual or estrous cycle. Although the synthesis and release of pituitary gonadotropins are affected by a number of endocrine, paracrine, and autocrine factors, the most important influence appears to be that of the hypothalamic decapeptide, gonadotropin-releasing hormone (GnRH). The tight inter-relationship between GnRH release and gonadotropin production is evidenced in patients with Kallmann's syndrome, in which GnRH deficiency results in low gonadotropin levels, absence of pubertal maturation, and infertility (42). Thus, GnRH is an essential coordinator of reproductive function.Regulation of gonadotropin biosynthesis and secretion by GnRH is critically dependent on GnRH delivery to the anterior pituitary. Pulsatile GnRH results in the stimulation of gonadotropin subunit mRNA levels and of LH and FSH secretion, whereas continuous exposure to GnRH downregulates mRNA levels and secretion (2, 45). Furthermore, the frequency and amplitude of GnRH pulses varies temporally and developmentally, for example, during different phases of the menst...

Effects of polymorphisms in gonadotropin and gonadotropin receptor genes on reproductive function

“…Maybe due to its crucial role in the regulation of fertility, the FSHB gene sequence is highly conserved in humans [75,121] and very few inactivating mutations were detected [75,[122][123][124][125][126][127][128][129][130][131][132]. Consistent with its high conservation rate, the most frequent variants of the FSHB gene are only five worlwide, but only two are carried by about 96.6% of population samples chosen in three continents [121].…”

Growth Differentiation Factor 9 (GDF9) Forms an Incoherent Feed-forward Loop Modulating Follicle-stimulating Hormone β-Subunit (FSHβ) Gene Expression

“…Conversely, recent work has revealed that at low pulse frequency the PKA-dependent pathway mediates GnRH activation of the cAMP response element-binding protein (CREB), which results in stimulation of FSH␤ transcription (11). cAMP early repressor is thought to abrogate the preferential stimulation of FSH␤ gene expression at high GnRH pulse frequency by reducing CREB occupation of the rat FSH␤ promoter (6). In contrast, differential expression of AP1 factors and corepressors SKIL and TGIF1 was proposed to mediate GnRH pulse sensitivity of FSH␤ expression (9).…”

“…The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession number GSE52631 syndrome, and underlie the pharmacological treatment of gonadal hormone-dependent diseases, such as endometriosis and prostate cancer. Because of its biological and medical importance, the frequency system underlying gonadotropin regulation has been an area of study for decades, and several factors have been proposed to contribute to FSH␤ frequency sensitivity (2,(5)(6)(7)(8)(9)(10)(11). The major information processing properties of molecular signaling networks are largely determined by simple network motifs, and specific feedback or feed-forward circuits are necessary to create a robust low frequency detector (12)(13)(14).…”

Decoding GnRH neurohormone pulse frequency by convergent signalling modules

“…phosphorylation, ubiquitination or sumoylation of TFs) with the potential to alter the efficiency of assembly and the stability of the multiprotein complex. It has been very well established experimentally that high GnRH pulse frequencies favour activation of the LHb promoter whereas slower pulse frequencies favour activation of the FSHb promoter both in vivo and in vitro [2,6,32,38] but the possibility that these optima themselves vary under different conditions has not been extensively explored. Thus, optimal pulse frequencies for GnRH effects differ between species [6] but to our knowledge, the possibility that they vary under different physiological conditions (i.e.…”