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Departments of Physiology3
and Internal Medicine,4 University of Virginia, Charlottesville, Virginia 22908
The frequency of gonadotropin-releasing hormone (GNRH1, or GnRH) pulses secreted from the hypothalamus determine the ratios of the gonadotropin subunit genes luteinizing hormone beta (Lhb), follicle-stimulating hormone beta (Fshb) and the common alpha-glycoprotein subunit gene (Cga) transcribed in the anterior pituitaries of mammals. Fshb is preferentially transcribed at slower GNRH1 pulse frequencies, whereas Lhb and Cga are preferentially transcribed at more rapid pulse frequencies. Producing the gonadotropins in the correct proportions is critical for normal fertility. Currently, there is no definitive explanation for how GNRH1 pulses differentially activate gonadotropin subunit gene transcription. Several pathways may contribute to this regulation. For example, GNRH1-regulated GNRH1-receptor concentrations may lead to variable signaling pathway activation. Several signaling pathways are activated by GnRH, including mitogen-activated protein kinase, protein kinase C, calcium influx, and calcium-calmodulin kinase, and these may be preferentially regulated under certain conditions. In addition, some signaling proteins feed back to downregulate their own levels. Other arms of gonadotroph signaling appear to be regulated by synthesis, modification, and degradation of either transcription factors or regulatory proteins. Finally, the dynamic binding of proteins to the chromatin, and how that might be regulated by chromatin-modifying proteins, is addressed. Oscillations in expression, modification, and chromatin binding of the proteins involved in gonadotropin gene expression are likely a link between GNRH1 pulsatility and differential gonadotropin transcription.
follicle-stimulating hormone, gonadotropin-releasing hormone, luteinizing hormone, mechanisms of hormone action
Much of the endocrine system is governed by rhythms, some of which are intrinsic and others that are influenced by the environment. Those rhythms that are longer than 24 h, the infradian rhythms, include the seasonal breeding patterns in some animals and the female menstrual cycle [1]. Circadian or 24-h rhythms include the sleep-wake cycle and the increase in gonadotropin secretion seen at night in adolescents [2]. Finally, there are the cycles of less than 24 h, the ultradian cycles, such as the pulsatile release of LH, FSH, growth hormone, and prolactin [1, 3].
The reproductive axis is a finely-controlled system consisting of three endocrine organs: the hypothalamus, pituitary, and gonads. Each of these organs secretes hormones critical for normal reproduction. These hormones feed back at multiple levels of the reproductive axis to control their own synthesis and secretion, resulting in a tightly-regulated system. Specific, widely-scattered neurons in the hypothalamus secrete the decapeptide gonadotropin-releasing hormone (GNRH1) in an episodic pattern of pulses. GNRH1 travels through the hypophysial portal blood system to the anterior pituitary, where it binds GNRH1-regulated GNRH1-receptor (GNRHR) on the cell surface of the gonadotropes [1].
The frequency of GNRH1 pulses varies widely over the female menstrual cycle, and in both males and females through the many stages of reproductive development [2]. Secretion of LH and FSH at the appropriate frequency and amplitude is critical for normal fertility in the female. A slow GNRH1 pulse frequency favors increased secretion of FSH, leading to development of the ovarian follicle during the follicular phase of the menstrual cycle. An abrupt increase in LH in response to rapid, high-amplitude GNRH1 pulses is required for ovulation of an egg from the ovaries, marking the beginning of the luteal phase of the cycle [4]. Following ovulation, high levels of estrogen and progesterone secreted by the corpus luteum feed back to the hypothalamus and inhibit GNRH1 pulses and LH and FSH secretion. Corpus luteum atresia with the accompanying fall in the steroid hormones restarts the cycle, allowing the slow GNRH1 pulse frequency required for FSH release and recruitment of the next follicle. In pathological states, constant GNRH1 suppresses pituitary secretion of LH and FSH, and restoration of GNRH1 pulses restores pulsatile secretion [5].
The pituitary gonadotropins, LH and FSH, are glycoprotein dimers composed of an alpha glycoprotein subunit (CGA), common to LH, FSH and thyroid-stimulating hormone, and unique beta subunits [1]. In rodent models, the frequency of the GNRH1 pulses determines the predominant subunit gene transcribed at any given time (Fig. 1) [8]. Cga is preferentially transcribed at high GNRH1 pulse frequencies of one pulse every 8–30 min, but the mRNA is also synthesized at slower pulse frequencies. The Lhb subunit gene is transcribed at intermediate GNRH1 pulse frequencies of one per 30–60 min, and transcription of the Fshb subunit gene is favored at the slowest pulse interval, one per 120–240 min [8, 9]. The events leading up to each burst of gonadotropin transcription likely have a rhythmic nature as well. A fundamental question in the field of gonadotropin regulation is: how does the pulse frequency of GNRH1 differentially regulate the three gonadotropin subunits? This regulation appears to be governed by at least three rhythmic subcellular mechanisms: signaling pathways are stimulated and suppressed, proteins are made and destroyed, and transcription factors bind and release DNA.
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Recent focused microarray studies from the laboratory of Dr. Stuart Sealfon, measuring transcription of selected genes, demonstrated that many mRNAs in the gonadotroph, in addition to the gonadotropins, are regulated by GNRH1, as discussed below [15–17]. By analyzing large panels of mRNA at both early (1 h) and late (3–6 h) time points following GNRH1 stimulation, these data suggest a large number of potential signaling feedback loops that are initiated by GNRH1 stimulation. The microarray studies measure only new mRNA transcripts, and most suggested targets are awaiting more detailed analysis to determine physiological relevance. These data do, however, provide suggestions of how signaling in the gonadotroph is rapidly initiated and terminated, characteristics required for a system regulated by changes in pulse frequency.
Binding of GNRH1 to its cellular G-protein-coupled receptor initiates several intracellular signaling pathways, including phospholipase C, calcium influx and release from intracellular stores, inositol 1,4,5-triphosphate (IP3), PRKCC (also known as PKC), and mitogen-activated protein kinase (MAPK1) (reviewed in [16]). Starting at the first point of GNRH1 signaling, binding of GNRH1 to GNRHR, GNRH1 appears to initiate downregulation of the GNRH1 response. This is indicated by the upregulation of mRNA for Rgs2 (regulators of G-protein signaling-2), a GTPase activating protein (GAP) that specifically acts to shorten the duration of signaling of GNAQ and GNA11 (also known as G
q and G11) [15, 18, 19]. PRKCC, in turn, is able to phosphorylate RGS2, resulting in downregulation of the GAP [18]. This cycle holds the potential for a pulse of GNRH1 to first stimulate the protein that restrains further signaling and then quickly remove that signal through phosphorylation, resetting the system for the next pulse of GNRH1. This would seem to be an especially necessary regulatory mechanism for GNRHR, which, in contrast to most G-protein-coupled receptors, does not have an intracellular C-terminus to be used for desensitization and internalization [20]. If the signaling molecules downstream of GNRHR decode the GNRH1 pulse frequency, then it may be important to have a quickly recovering GNRHR. Regulation by RGS proteins may provide the control over receptor refractory time required for transmission of pulse frequency information to the transcription machinery.
Calcium, another major signaling pathway stimulated by GNRH1, is potentially regulated by several different mechanisms. Activation of GNRHR by GNRH1 results in a two-phase increase in calcium concentration. The spike phase is driven by ITPR1 (also known as the IP3 receptor)-mediated release of intracellular calcium stores, whereas opening of voltage-gated calcium channels causes the second, sustained phase [21, 22]. Several pieces of data provide clues to explain how both of these phases of the calcium signal could be rapidly downregulated by GNRH1-triggered events.
With as little as 5 min of GNRH1 pretreatment, there is a loss of the spike phase of calcium release in response to a subsequent stimulation by GNRH1 [23]. These authors [23] showed that this loss of GNRH1 sensitivity coincided with proteasome-mediated degradation of ITPR1. The loss of receptor, as measured by Western immunoblot, took several hours to recover. Intracellular calcium stores remained intact, and the ITPR1 sensitizing agent thimerosal was able to increase IP3-mediated calcium mobilization in response to high doses of GNRH1. This suggests that intracellular calcium stores could be available a short time after a pulse, when amplitude is high, but unavailable to lower-amplitude pulses. Because these experiments were conducted with supraphysiological doses of GNRH1, the time to and pattern of recovery in response to physiological pattern and doses of GNRH1 are difficult to estimate [23]. It would be useful to know whether GNRH1 induces new IP3 at physiological levels, suggesting a cycle of ITPR1 creation and destruction.
The mRNA for Gem (also referred to as Kir), a calcium signaling pathway-associated protein, was shown in microarray analysis to be upregulated by GNRH1 [15]. GEM is a small G-protein that is highly expressed in the pituitary and binds to and inhibits L-type calcium channels [24]. In addition to upregulation of the Gem mRNA with GNRH1 treatment, the protein itself is activated by calcium-bound calmodulin [24]. This could potentially create a negative feedback loop to limit GNRH1 stimulation of gene transcription via calcium by the sustained phase of calcium release.
Intermediary molecules stimulated by calcium might also be regulated to confer pulsatile transcription of the gonadotropin genes. The calcium calmodulin kinase CAMK2 is one such intermediary, and by its mode of activation is an attractive candidate for conveying information encoded by calcium oscillations. CAMK2 requires two molecules of calcium-bound calmodulin (Ca-CALM1) to bind to the enzyme for activation [25, 26]. The higher the frequency of calcium oscillations, the higher the percentage of CAMK2 activated [27]. This is likely because, at higher frequency pulses, there is less time for Ca-CALM1 to dissociate from a CAMK2 molecule while awaiting binding of a second Ca-CALM1. Longer durations of stimulation and higher amplitude calcium pulses also increase the percentage of activated CAMK2 [27]. The above study was conducted with immobilized CAMK2, saturating concentrations of calcium, and pulses of calmodulin, rather than with an agonist-based/receptor-mediated system, making the data difficult to extrapolate. Data obtained in rodent and clonal gonadotroph cells point to CAMK2 as an important mediator for gonadotropin transcription [11, 12], but whether the enzyme is able to directly transmit GNRH1 frequency into differential gene activation is unclear.
CAMK2 is activated by GNRH1 in a calcium-dependent manner in the LßT2 clonal mouse gonadotroph cell line [12]. In addition, CAMK2 is able to stimulate the promoters of both Lhb and Cga [12]. In studies using multiple 10-sec pulses of GNRH1 on primary pituitary cultures, primary transcripts of Cga, Lhb, and Fshb were all inhibited by inhibition of CAMK2, with Cga being the most suppressed [11]. A 10-sec GNRH1 pulse results in calcium oscillations in the cell for approximately 70 sec after removal of the stimulus [28]. Following addition of constant GNRH1, maximum CAMK2 phosphorylation occurs between 2 and 5 min and returns to basal by 45 min in both LßT2 cells and primary pituitary cells [11, 12]. This suggests that calcium is released in a time frame appropriate for stimulation of CAMK2 phosphorylation and that CAMK2 may then contribute to the longevity of the GNRH1 signal. When considering that physiological GNRH1 pulse intervals are on the scale of 8–240 min, CAMK2 is active at pulse intervals that favor Cga and Lhb, but not Fshb, transcription (Figs.1 and 2) [8, 9]. This suggests that decay of CAMK2 activity, rather than differences in activation of the enzyme, is important for regulating gonadotropin expression.
Another arm of GNRH1 signaling that has been studied extensively is stimulation of the MAP2K1 (also known as MEK1)-MAPK1 signaling pathway. Both Fshb and Cga are stimulated in part by activation of MAP2K1 signaling [13, 29–31]. Interestingly, the MAPK pathways are activated downstream of calmodulin, but not CAMK2, stimulation [32]. Two phosphatases that inactivate MAPK1, DUSP1 and DUSP4 (also known as MAPK phosphatase 1 and 2 respectively), are upregulated in response to GNRH1 [15, 33], but the GNRH1 pulse requirement is unknown. This has particular significance because the frequency of GNRH1 pulses has recently been shown to affect the duration of MAPK1 activation (Fig. 1) [14]. In addition, overexpression of DUSP1 and DUSP4 downregulated Cga promoter expression in the T3 gonadotroph cell line [33]. It is conceivable that DUSP1 or DUSP4 could be activated at faster frequencies than MAPK1, causing inhibition of MAPK1 at these faster frequencies, but that they fail to cross the activation threshold at slower frequencies because of rapid degradation (Fig. 2). Because MAPK1 activation is important for Fshb transcription, it is possible that activation of DUSP1 and DUSP4 at shorter GNRH1 pulse intervals might prevent Fshb transcription via a decrease in MAPK1 activity. Lhb transcription in primary rodent gonadotroph cells does not require MAPK1 [13], and would be unaffected by an increase in DUSP activity at the faster intervals. Cga, which is also stimulated by the MAPK1 pathway, is generally less dependent on GNRH1 pulse frequency, maintaining a constant basal expression level in pituitary gonadotropes throughout the estrous cycle [34]. It is likely that Cga would be less affected by inhibition of MAPK1 at higher frequency pulses than Fshb. Upregulation of DUSP1 and DUSP4 at shorter GNRH1 pulse intervals would suggest that increased pulse frequency specifically inhibits Fshb gene transcription rather than preferentially stimulating Lhb and Cga gene transcription.
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Although GNRHR is not internalized like most G-protein-coupled receptors, control of the density of GNRHR on the cell surface may play an important role in controlling which signaling pathways are stimulated in response to GNRH1. GNRHR number is regulated by GNRH1 pulses throughout the rat estrous cycle, peaking when GNRH1 pulse intervals are approximately 30 min apart, the same as the time of maximum Lhb gene transcription and the LH surge [8, 35, 36]. In support of the notion that GNRHR density impacts gonadotropin gene transcription at a given pulse frequency, Kaiser et al. [37] used GNRHR-null GH3 cells stably expressing different levels of GNRHR to measure gonadotropin synthesis, and found that at increased GNRHR levels there is an increase in Cga and Lhb, but not Fshb, promoter stimulation. A later study in LßT2 cells found that increasing GNRH1 pulse frequency increased GNRHR density, which preceded an increase in Lhb promoter stimulation and a dampening of Fshb promoter stimulation by GNRH1 [38]. Similar results were observed when GNRHR was artificially overexpressed by transient transfection of the cells. At this point, it is not known whether the increase in GNRHR number results in differential coupling of the receptor to G proteins. The best evidence to indicate this possibility is a study that found that the GNRHR is able to couple both GNAQ and GNAS (also known as Gq and Gs), supporting the possibility that differential coupling could occur [39].
Other GNRH1-responsive proteins whose expression may be dynamically regulated are transcription factors. Currently, transcription factors known to be stimulated by GNRH1 and to act on the gonadotropin genes are ATF3, which stimulates the human CGA gene, and EGR1 (Egr-1) [40]. The Lhb promoters of all species tested contain two EGR1-binding sites, which are required for full activation of the promoter; EGR1 binding is selective for Lhb among the gonadotropins [41, 42]. In unstimulated T3 and LßT2 cells, EGR1 is almost undetectable, is maximally induced 1 h after stimulation, and returns to basal expression levels after more than 4 h of constant GNRH1 treatment [43] (unpublished results). This time scale, if superimposed on the GNRH1 pulse intervals required for gonadotropin stimulation in rat pituitaries, would suggest that there is adequate EGR1 in the cells to stimulate Lhb transcription at even the longest physiological pulse intervals. However, because these cell lines are able to respond to both pulsatile and continuous GNRH1 treatment, EGR1 half-life could be altered in these systems. EGR1 can be degraded by the proteasome, and examination of EGR1 protein levels in primary cultures in response to pulses of GNRH1, as well as measurement of protein half-life in both systems, would provide insight into the necessity of temporal regulation of EGR1 protein [44].
Posttranslational modification, rather than changes in protein expression, likely regulates gonadotropin transcription mediated by the orphan nuclear receptor NR5A1 (also known as steroidogenic factor-1). Although NR5A1 protein levels do not change significantly when LßT2 cells are treated with GNRH1 or the cAMP stimulator forskolin (unpublished results), these signals may regulate NR5A1 activity. The work on the Cyp17a1 promoter presents a model of reduced DNA binding by NR5A1 and increased transcription in the face of a cAMP challenge [45]. This parallels data seen for estrogen, which binds estrogen receptor 1 and stimulates transcription, but also targets the receptor for proteasome-mediated degradation [46]. Without degradation by the ubiquitin-proteasome pathway, estrogen-mediated transcription is halted. Our laboratory has recently demonstrated that the E3 ligase RNF4 (also known as small nuclear RING finger protein) acts as a coactivator, increasing Lhb but not Cga transcription [47, 48]. We also demonstrated that RNF4 is able to bind both NR5A1 and SP1, factors important in Lhb gene transcription. This suggests the possibility that RNF4 ubiquitination of NR5A1 could play a role in the regulation of this nuclear receptor. This hypothesis is further supported by recent data that an E2 ligase, UBE2D2, is upregulated in response to GNRH1 and estrogen, and is important for estrogen-mediated Lhb gene transcription [49]. Their work demonstrates increased Lhb transcription in response to increased UBE2D2 expression and estrogen receptor 1 degradation. The NR5A1 promoter-binding sites were required for estrogen-mediated stimulation of Lhb transcription. Ubiquitination of NR5A1 in response to UBE2D2 activation has not yet been addressed. It has been suggested that increased monoubiquitination may preferentially activate certain transcription factors, whereas polyubiquitination may preferentially direct proteins to the proteasome degradation pathway [50]. Thus, increased ubiquitination could play an important role in transcription factor activity, even in the absence of significant protein degradation. Either way, modification and/or turnover of nuclear receptors mediated by an ubiquitination complex containing RNF4 and UBE2D2 could contribute to Lhb gene transcription. Interestingly, NR5A1 binds to and appears to be required for expression of several genes, including Cga, Lhb, Fshb, and Gnrhr [51]. It is currently unknown whether or how this protein would be differentially regulated on these genes.
Naturally occurring mutations in the human NR5A1 gene provide us with further insights into the regulation of NR5A1. The NR5A1 mutant, NR5A1G35E, leads to adrenal failure and XY sex reversal because of lack of gonadal development [52]. The patient in whom this mutation was first identified was heterozygous, suggesting that dosage is critical for NR5A1 function. NR5A1G35E is unable to bind to several NR5A1 consensus sites in vitro, including the promoters for Lhb, Cyp11a1, and Nr0b1 (also known as Dax1) [52–54]. NR5A1G35E retains the ability to bind to several other NR5A1 consensus sites, including the Amh and Cyp19a1 (also known as Mis and aromatase, respectively) promoters. A dependence on modification of the NR5A1 DNA-binding domain may be the distinguishing feature between promoters that NR5A1G35E can and cannot bind. Protein kinase A stimulation of KGN human ovarian granulosa cells causes NR5A1 to reorganize in the nucleus into discrete foci, but the NR5A1G35E mutant cannot do this [55]. Glycine 35 is adjacent to a lysine, which is a candidate PCAF acetylation site that increases NR5A1 transcriptional activity [56]. It may be that the polar, acidic glutamic acid that was substituted for the neutral glycine prevents acetylation of lysine 34, decreasing binding of NR5A1G35E to promoters of genes such as Lhb. Dependence on modification of this site is a potential point of divergence in NR5A1 regulation of the gonadotropin genes.
The role of chromatin modification is emerging as a critical component in the regulation of gene transcription. In vivo, DNA is found coiled around histones in chromatin. These histones serve both to compact the DNA and to silence parts of it. The histone core is composed of 8 subunits, 2 each of H2A, H2B, H3 and H4. Each subunit has an exposed tail region, which can be modified by phosphorylation, acetylation, ubiquitinylation, or methylation (reviewed in [57]). These modifications alter the charge of the histone, resulting in altered binding to the DNA, and also create binding sites for large transcriptional complexes, such as SWI/SNF, which use ATPase activity to disrupt nucleosome structure and facilitate transcription [57, 58]. Histone modifications are carried out by a series of enzymes specific to the modification. The best-studied of these enzymes are those that add or remove acetyl groups, the histone acetyltransferases (HATs) and histone deacetylases respectively. Sequential binding of ligand-bound receptor, followed by receptor coactivators, HATs, and RNA polymerase, occurs with a defined periodicity for different nuclear receptors [46, 59]. The potential for other transcription factors to bind to the promoters of specific gonadotropin genes with differential periodicities is intriguing, and remains to be determined. At least one transcription factor, NR5A1, binds the promoters of all three gonadotropin subunit genes, and its association under basal and GNRH1-stimulated conditions could be of particular interest.
Few studies on chromatin structure have been published in the gonadotropin field; however, one study by Mouillet et al. [60] highlights the need for an expanded knowledge of chromatin regulation. In this study, the authors showed that the HAT EP300 (also known as p300) was able to associate with the Lhb promoter in LßT2 cells using a chromatin immunoprecipitation assay. In addition, they showed that there was a 2-fold increase in EP300 association with the Lhb promoter in response to GNRH1. Finally, they showed dramatic stimulation of Lhb promoter activation in heterolgous CV-1 cells with the introduction of transfected EP300, EGR1, and NR5A1, with a more modest 2-fold increase in promoter activity in LßT2 cells with overexpression of EP300, EGR1, and NR5A1. This is in contrast to transient transfection data from our laboratory and others that showed no effect of EP300 overexpression on Lhb promoter activation in the absence of EGR1 and NR5A1 overexpression. [41]. Likely reasons for these discrepancies are twofold. First, EP300 enhances transcription by acetylating histones [61]. Model promoter-reporter constructs may not be efficiently arranged into chromatin structures, and may thus respond inappropriately to increased levels of chromatin-modifying proteins. This lack of chromatin compaction may account for a reduced or artificial requirement for chromatin remodeling enzymes, and may alter the importance of transcription factor-binding sites in promoter-reporter assays compared to chromatin association studies. Second, other relevant transcription factors may need to be overexpressed in addition to EP300 for the changes in promoter activity of transfected plasmid constructs in LßT2 cells to be seen. Additional studies with chromatin immunoprecipitation or other approaches to accurately asses the state and activity of endogenous genes will be helpful in understanding the physiological role of these factors and other proposed regulatory mechanisms.
There are several potential mechanisms for regulation of the gonadotropin gene promoters. Signaling pathways stimulated by GNRH1 may induce transcription factor and/or coactivator synthesis, cause posttranslational modifications of transcription factors, or modify the chromatin to allow transcription factors to bind. We suggest that protein latency contributes to the differential regulation of the gonadotropin subunit genes through all of these mechanisms. Herein (Fig. 2), we present a model that could apply to MAPK1, EGR1, or any other protein that differentially contributes to gonadotropin transcription. Using MAPK1 as a possible example, at fast-frequency pulses MAPK1 is rapidly stimulated (Fig. 2A). The protein level quickly crosses the threshold required for stimulation of Cga and Fshb gene transcription. At the same time, proteins with inhibitory activity, such as DUSP1, are made and act to inhibit MAPK1. As the pulse intervals increase, proteins such as MAPK1 may still be able to cross a threshold level and stimulate transcription (Fig. 2B), whereas inhibitors may require shorter pulse latency and therefore never reach high enough levels to cause significant inhibition. This could result in maximal MAPK1 activity at the slower GNRH1 pulse intervals most conducive to Fshb gene transcription. This idea of latency should also apply to the stimulatory proteins. At slow-frequency pulses, factors important for Lhb transcription, such as CAMK2, may decay during the longer pulse intervals, preventing the protein from reaching levels adequate to stimulate transcription (Fig. 2C). Depending on the required latencies of various proteins, the ability of GNRH1 to stimulate activators and inhibitors for those proteins, and the requirement of the proteins for regulation of the three promoters, a change in pulse interval may affect a change in the gonadotropin genes transcribed.
1 Supported by the NICHD/NIH through cooperative agreement (U54 HD28934) as part of the Specialized Cooperative Centers Program in Reproduction Research. 
2 Correspondence: Margaret A. Shupnik, Department of Internal Medicine/Endocrinology, PO Box 800578 HSC, University of Virginia, Charlottesville, VA 22908. FAX: 434 982 0088; mas3x{at}virginia.edu
Received: 3 November 2005.
First decision: 3 December 2005.
Accepted: 3 February 2006.
-subunit promoter by gonadotropin-releasing hormone. Mol Endocrinol 2005 19:2624-2638This article has been cited by other articles:
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