Molecular Endocrinology, doi:10.1210/me.2007-0515
Molecular Endocrinology 22 (6): 1295-1303
Copyright © 2008 by The Endocrine Society
Welcoming β-Catenin to the Gonadotropin-Releasing Hormone Transcriptional Network in Gonadotropes
Travis B. Salisbury1,
April K. Binder1 and
John H. Nilson
School of Molecular Biosciences, Washington State University, Pullman, Washington 99164-4660
Address all correspondence and requests for reprints to: John H. Nilson, School of Molecular Biosciences, 639 Fulmer Hall, Washington State University, Pullman, Washington 99164-4660. E-mail: jhn{at}wsu.edu.
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ABSTRACT
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GnRH binds its G-coupled protein receptor, GnRHR, on pituitary gonadotropes and stimulates transcription of Cga, Lhb, and Fshb. These three genes encode two heterodimeric glycoprotein hormones, LH and FSH, that act as gonadotropins by regulating gametogenesis and steroidogenesis in both the testes and ovary. GnRH also regulates transcription of Gnrhr. Thus, regulated expression of Cga, Lhb, Fshb, and Gnrhr provides a genomic signature unique to functional gonadotropes. Steadily increasing evidence now indicates that GnRH regulates transcription of its four signature genes indirectly through a hierarchical transcriptional network that includes distinct subclasses of DNA-binding proteins that comprise the immediate early gene (IEG) family. These IEGs, in turn, confer hormonal responsiveness to the four signature genes. Although the IEGs confer responsiveness to GnRH, they cannot act alone. Instead, additional DNA-binding proteins, including the orphan nuclear receptor steroidogenic factor 1, act permissively to allow the four signature genes to respond to GnRH-induced changes in IEG levels. Emerging new findings now indicate that β-catenin, a transcriptional coactivator and member of the canonical WNT signaling pathway, also plays an essential role in transducing the GnRH signal by interacting with multiple DNA-binding proteins in gonadotropes. Herein we propose that these interactions with β-catenin define a multicomponent transcriptional network required for regulated expression of the four signature genes of the gonadotrope, Cga, Lhb, Fshb, and Gnrhr.
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A SHORT HISTORY OF THE GnRH TRANSCRIPTIONAL NETWORK IN GONADOTROPES
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GnRH SIGNALS THROUGH several MAPK cascades to regulate transcription of at least 75 genes (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). Genes regulated by GnRH organize into a tiered hierarchy (primary, secondary, and tertiary) based on the kinetics of their response to GnRH with selected examples depicted in Fig. 1
. Culmination of the GnRH transcriptional signal results in regulated expression of four tertiary gonadotrope signature genes: Cga, Lhb, Fshb and Gnrhr.
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Fig. 1. Selected Overview of the GnRH Transcriptional Network in Gonadotropes
GnRH activation of MAPK signaling cascades rapidly increases the transcription of several primary response genes including Egr1, Atf3, and Jun (colored squares). These genes encode DNA-binding immediate early proteins (IEG; colored shapes) that confer GnRH responsiveness to secondary genes such as Mkp2/Dusp4 and tertiary genes including Lhb, Cga, Fshb, and Gnrhr. The orphan nuclear receptor SF1 binds to the promoters of all four signature genes and acts permissively to render each gene responsive to GnRH. Recent evidence suggests that members of the TCF/LEF family of DNA-binding proteins may also mediate the transcriptional effect of GnRH on select genes such as Jun.
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Egr1, Jun, and Atf3 are members of the immediate early gene (IEG) family (19). Early growth response protein 1 (EGR1) belongs to the zinc-finger C2H2 subfamily of IEGs whereas JUN and activating transcription factor 3 (ATF3) are members of the basic-leucine zipper subfamily. The IEGs typify primary response genes because detectable changes in transcription occur within 1 h of GnRH stimulation (13, 14). As DNA-binding proteins, their accumulation transfers GnRH responsiveness to both secondary and tertiary genes that contain the appropriate DNA response elements. For example, as EGR1 accumulates, it then regulates transcription of secondary response genes such as MAPK phosphatase 2 (Mkp2), also referred to as dual specificity phosphatase 4 (Dusp4) (20) and ultimately Lhb (21, 22, 23, 24, 25, 26, 27) (Fig. 1
). EGR1 also regulates primary response genes like Atf3 (28, 29) and displays a positive autoregulatory loop with its own gene (30, 31). Thus, EGR1 confers GnRH responsiveness to a number of genes that make up the hierarchical transcriptional network in gonadotropes including one of the signature genes, Lhb.
GnRH also confers hormonal responsiveness to three (Cga, Fshb, and Gnrhr) of the four tertiary genes by acting through activator protein 1 (AP1) (3, 4, 32, 33, 34, 35, 36). AP1 heterodimers always contain a JUN subunit (37), and GnRH signals through JUN N-terminal kinase (JNK) to increase activity of AP1 (4, 12, 38). ATF3 also confers GnRH responsiveness to Cga by forming a heterodimer with JUN and then binding to tandem cAMP response elements in the human promoter (4). Expression of Atf3 mRNA and activity of ATF3 protein is further enhanced by GnRH signaling through ERK and JNK (4). JUN, like EGR1, also establishes a positive autoregulatory loop with its own gene (39). In addition to these gene-gene relationships, the GnRH transcriptional signal also flows back to negatively regulate selected members of the MAPK cascades (20, 40). For instance, GnRH stimulated increases in Mkp2/Dusp4 culminates ultimately in inactivation of JNK and partial inactivation of ERK (40).
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GnRH REGULATION OF THE FOUR SIGNATURE GENES REQUIRES STEROIDOGENIC FACTOR 1 (SF1)
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Response elements for the orphan nuclear receptor SF1 are found in the promoter regions of all four signature genes (32). SF1 plays a vital role in the GnRH transcriptional network (41, 42, 43) even though the orphan nuclear receptor appears refractory to regulation by the neurohormone (22, 23, 26, 44, 45). For instance, pulses of GnRH dynamically regulate transcription of mammalian Lhb genes (46, 47, 48, 49). This dynamic regulation, however, represents a tertiary response to GnRH mediated by the more rapid induction of Egr1 transcription and protein synthesis (13, 14, 15, 16, 22). Because levels of SF1 remain unresponsive to changes in GnRH, EGR1 is viewed as the primary determinant of hormone-induced transcriptional fluxes of Lhb (22, 23, 26, 44, 45). Nevertheless, GnRH induction of EGR1 is not sufficient for ensuring that LH reaches the necessary levels required for physiological activity in transgenic mice with SF1-deficient gonadotropes (42, 43). These mice are hypogonadal and fail to express detectable levels of Cga, Lhb, Fshb, and Gnrhr and are infertile (42, 43). In contrast, conflicting phenotypes have been reported for EGR1-deficient males generated with different targeting constructs (50, 51, 52). LH levels are reduced whereas fertility is impaired in one but not the other. Whereas there are several possible explanations for this difference in fertility, lowered levels of LH and Lhb mRNA are consistent with the notion that SF1 acts permissively to render Lhb responsive to GnRH-induced changes in EGR1. We predict that a permissive role of SF1 will extend to the three other signature genes that are regulated by GnRH-induced changes in DNA-binding proteins encoded by other IEGs.
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A SURPRISING LINK BETWEEN SF1, β-CATENIN, AND GnRH-REGULATED GENE EXPRESSION IN GONADOTROPES
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β-Catenin is a transcriptional coactivator typically associated with T cell factor (TCF)/lymphoid enhancer factor (LEF)-responsive genes regulated by the WNT family of secreted glycoproteins (53, 54). The binding of β-catenin to TCF/LEF causes release of histone deacetylase and corepressors such as Groucho (officially GPRK2) and subsequent recruitment of additional coactivators and chromatin-remodeling proteins like p300/cAMP response element-binding protein-binding protein and Brahma-related gene 1, respectively (53, 54, 55, 56, 57). These collective interactions confer transcriptional competency to TCF/LEF (53, 54, 55, 56, 57).
Growing evidence indicates that β-catenin also coactivates a number of transcriptional proteins including IQ motif containing GFTase-activating protein (58), paired-like homeodomain factor 1 (55), paired-like homeodomain transcription factor (PITX) 2 (59), androgen receptor (60, 61), forkhead box O (62), members of the SRY HMG box family (63), and the basic-leucine zipper proteins JUN and FOS (37). Additional reports indicate that β-catenin acts as a coactivator of SF1 when it transduces WNT signals to Dax1 (officially NR0B1) and inhibin 
(officially Inha) (64, 65). Coactivation of SF1 occurs through the binding of β-catenin to a cluster of amino acids (235–238) located in the first helix of the putative ligand-binding domain of the orphan nuclear receptor that also contains the activation function 1 domain (65, 66). β-Catenin, through an interaction with SF1, has also been shown to mediate FSH-stimulated increases in aromatase gene expression in granulosa cells (67). Together, these reports suggest that β-catenin may serve as a required coactivator for many SF1-dependent genes.
Recently, we reported that GnRH regulation of Lhb gene expression in gonadotrope-derived LβT2 cells requires a functional interaction between β-catenin and SF1 (44). Lines of evidence supporting this conclusion included the following: 1) reduction of β-catenin in LβT2 cells through overexpression of axin 1 (AXIN) or through use of a pool of short interfering RNA specific to β-catenin reduced GnRH-stimulated activity of an LHB promoter reporter construct; 2) overexpression of β-catenin increased the transactivation activity of SF1 and EGR1, as well as their functional interaction; 3) conversely, short interfering RNA specific for β-catenin attenuated the activity of SF1 and EGR1 as well as their functional interaction; 4) GnRH increased accumulation of β-catenin and its physical association with SF1 when analyzed by coimmunoprecipitation; 5) an SF1 mutant lacking a β-catenin-binding site acted in a dominant-negative fashion and almost completely abolished the functional synergism normally exhibited between SF1 and EGR1 (22, 26, 27, 45); and 6) GnRH enhanced the colocalization of β-catenin with the endogenous promoter region of the mouse Lhb gene that also binds SF1 and EGR1.
Together, the results enumerated above suggest that β-catenin serves as an essential coactivator of SF1 that renders the Lhb gene responsive to GnRH-induced changes in EGR1 as modeled in Fig. 2. In the absence of GnRH, we envision that the interaction between β-catenin and SF1, along with contributions from PITX1, another critical DNA-binding protein (22, 68, 69), maintains the Lhb gene in a poised state that has the potential to respond to GnRH. Levels of Lhb transcription in this poised state are low; analogous to the amount of light generated by a light dimmer when its controller is on but set to a low level. GnRH acts as a rheostat by increasing concentrations of EGR1 and thereby moving transcription from a poised to maximally active state of transcription. Because the GnRH-stimulated increase in EGR1 is transient and dependent on the concentration of the neurohormone that varies during pulsatile secretion (14, 46, 49, 70), transcriptional activity of the Lhb gene must return to the poised state as the concentration of the zinc-finger IEG wanes.
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Fig. 2. Contributions from β-Catenin Enable EGR1 to Act as a Rheostat that Regulates Expression of LHB/Lhb
Activity of SF1 requires binding of β-catenin. Contributions from this complex and other DNA-binding proteins such as PITX1 place the LHB/Lhb gene in a poised state with low transcriptional activity. As the concentration of EGR1 rises in response to the GnRH signal, transcriptional activity of the LHB/Lhb gene increases via synergistic interaction with β-catenin, SF1, and PITX1. β-cat, β-Catenin.
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As mentioned previously, expression of Cga, Fshb, and Gnrhr also requires SF1 (42, 43). Therefore, an important remaining question is whether these three gonadotrope genes also require a functional interaction between β-catenin and the orphan nuclear receptor. This question may be approachable through cre-recombinase-mediated recombination that targets deletion of β-catenin after embryonic specification of gonadotropes. If the transcriptional activity of SF1 requires its interaction with β-catenin in vivo, then mice harboring this deletion should lose expression of all four signature genes. As an alternative approach, mice that overexpress wild-type SF1 or a variant incapable of binding β-catenin should provide opposing phenotypes allowing further assessment of the physiological importance of the functional interaction between β-catenin and SF1.
GnRH REGULATION OF TCF/LEF-DEPENDENT GENES IN GONADOTROPES: ANOTHER POTENTIAL SITE of β-CATENIN ACTION
GnRH stimulates expression of several known TCF target genes including Jun, Fra1, and Myc (13, 14, 53, 71, 72). A recent report from Gardner and colleagues (72) indicates that GnRH-stimulated increases in the mRNAs encoded by these three genes in LβT2 cells are associated with increased nuclear accumulation of β-catenin and increased activity of TOPflash, an artificial TCF-dependent reporter construct. Together these data suggest that GnRH-regulated expression of Jun, Fra1, and Myc requires a functional interaction between β-catenin and members of the TCF gene family. If so, then the JUN-responsive signature genes (Cga, Fshb, and Gnrhr) may be secondary targets of the GnRH-TCF pathway.
Clearly establishing the hierarchical placement of β-catenin and TCF will require additional experiments demonstrating that GnRH-regulated expression of Cga, Fshb, and Gnrhr is secondary to β-catenin- and TCF-dependent regulation of Jun transcription. The likelihood of this possibility is reinforced by the observation that the promoter-regulatory region of Jun harbors response elements for TCF, JUN1, and JUN2 (71). Jun has also been identified as one of the most TCF/LEF-responsive genes in hematopoietic and colon cancer cells (73, 74). Within the context of the Jun promoter, β-catenin, JUN, and TCF act cooperatively to stimulate transcription (71). These three proteins also bind to the Jun promoter when assayed using chromatin immunoprecipitation (71). Together these reports suggest that Jun may be a primary TCF/LEF gene target that is regulated by GnRH-stimulated changes in β-catenin. Pursuing this possibility is important because virtually all studies in gonadotropes reported to date have focused on signaling pathways that link GnRH to the terminal phosphorylation of JUN by JNK (4, 8, 18).
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WHO CARRIES THE GnRH SIGNAL TO β-CATENIN?
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Most GnRH signaling occurs through protein kinase C (PKC), which stimulates several MAPK cascades including JNK, ERK, and p38 MAPK (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 17, 18, 49). Prior reports have linked c-src tyrosine kinase (SRC), cell division cycle 42 (CDC42), and MAPK kinase 4/7 to neurohormonal regulation of JNK in gonadotrope-derived cell lines (6, 8, 18). GnRH induction of ERK is mediated by PKC and through MAPK kinase 1/2 because selective inhibition of this MAPK with either UO126 or PD98059 prevents ERK activation (3, 17). Finally, GnRH activation of p38 MAPK proceeds through PKC and possibly MAPK kinase 3/6 (2). A role for GnRH-stimulated calcium influx through the plasma membrane for activation of ERK but not JNK has also been reported (18, 75). These MAPK cascades activate many of the DNA-binding proteins that mediate the effect of GnRH on the primary, secondary, and tertiary response genes. As noted above, GnRH increases the nuclear accumulation of β-catenin (44, 72) followed by augmented binding of β-catenin and SF1 to the endogenous Lhb promoter-regulatory region in LβT2 cells (44). This begs the question of whether GnRH regulates accumulation of β-catenin through cross talk that occurs between its G-protein coupled receptor pathway and the canonical WNT/β-catenin signaling pathway.
Transcriptional effects of β-catenin are usually linked to the canonical WNT/frizzled/dishevelled (Fz/Dvl) pathway that promotes inhibition of a multiprotein complex containing AXIN, adenomatous polyposis coli, casein kinase I, and glycogen synthase kinase 3β (GSK3β) (53, 54) (shaded pathway; Fig. 3). There is, however, emerging evidence indicating that multiple G-protein coupled receptor signaling pathways including those regulated by PKC (76), protein kinase A (PKA) (77, 78), and phosphatidylinositol 3-kinase (PI3K) (79) can activate β-catenin independent of WNT signaling (Fig. 3). Thus, PKC, PKA, and PI3K must be considered as candidates that mediate GnRH regulation of β-catenin in gonadotropes through cross talk with the canonical WNT/β-catenin signaling pathway.
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Fig. 3. Potential Signaling Pathways for Permitting Cross Talk between WNT and GnRH
The shaded pathway represents the skeletal features of the canonical Wnt/β-catenin signal transduction pathway. Essential elements of known GnRH signaling cascades are depicted to the right of the shaded area. Solid arrows depict pathways where direct links have been established between known downstream components. Dotted arrows depict pathways where details that link upstream with downstream components remain incompletely characterized. We use the Jun promoter-regulatory region to illustrate how GnRH signals through JNK and potentially through β-catenin to regulate activity of a TCF-dependent promoter. APC, Adenomatous polyposis coli; Dvl, disheveled; FZ, frizzled; LRP, low-density lipoprotein receptor-related protein.
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Recent evidence indicates that GnRH stimulation of the TOPflash reporter in LβT2 cells can be blocked by pretreatment with either antide, a competitive inhibitor of GnRH, or with a metabolic inhibitor of Gq/11 (72). These results suggest that GnRH may regulate β-catenin via the PKC signaling pathway. This is consistent with another report indicating that PKC can enhance phosphorylation and thus inactivation of GSK3β (76). Whereas Gardner and colleagues (72) were unable to observe GnRH-dependent changes in GSK3β phosphorylation in LβT2 cells, we have preliminary data indicating a strong correlation between GnRH-induced increases in accumulation of β-catenin and S9 phosphorylation of GSK3β in LβT2 cells (our unpublished data; n = 3), leaving open the possibility that GnRH may signal through the PKC pathway to inhibit activity of GSK3β. GnRH activation of calcium-mediated single transduction through PKC is also a prominent signaling cascade activated by the neurohormone (18, 48, 75). Thus, a role for this signaling molecule for GnRH regulation of β-catenin may also exist in gonadotropes.
GSK3β can also be phosphorylated on S9 by AKT acting downstream of PI3K (76). Because GnRH can activate both SRC and epidermal growth factor receptor in T3 cells (8, 9, 80, 81), it is tempting to speculate these tyrosine kinases can lead to downstream activation of PI3K, phosphorylation and inactivation of GSK3β, and ultimately activation of β-catenin. However, there is little evidence indicating that GnRH activates PI3K in gonadotropes (82). In addition, metabolic inhibitors of PI3K fail to block GnRH-induced activity of a TOPflash reporter in LβT2 cells (72). Thus, if GnRH activation of SRC is involved in regulation of β-catenin, it may involve phosphorylation of GSK3β through CDC42 (Fig. 3). Although a direct effect of GnRH on CDC42 activity has not been reported to date, the neurohormone does increase SRC activity, which in turn has been shown to activate CDC42 in other cell systems (8, 83). Moreover, overexpressed dominant-negative CDC42 perturbs GnRH-stimulated increases in JNK activity, suggesting a functional role for this protein (8, 18). This notion is further supported by the proposal that CDC42 regulation of GSK3β phosphorylation modifies cellular levels of β-catenin in astrocytes (84).
GnRH also signals through PKA in gonadotropes (85, 86). In this regard, PKA-dependent phosphorylation of β-catenin on S675 and associated TOPflash activation has been reported in human embryonic kidney 293 and Cos-7 cells (77, 78). PKA can also directly phosphorylate GSK3β on S9, leading to inactivation and subsequent stabilization of β-catenin (76). Thus, PKA provides another potential route that would allow GnRH to regulate β-catenin.
Finally, it is important to consider the possibility that GnRH may inhibit GSK3β through a mechanism independent of S9 phosphorylation (76). For instance, phenotypic analysis of homozygous knock-in mice suggests that WNT signaling is not compromised by mutation of S9 to A9 in GSK3β (87). One explanation is that GSK3β binding partners such as Frat can also regulate the activity of the kinase (76). For instance, Frat, by binding to GSK3β, perturbs the interaction between the kinase and AXIN, which contributes to activation of β-catenin in WNT signaling (76). Alternatively, PGE2 stimulates activation of β-catenin in colon cancer cells through an interaction between Gs and AXIN that occurs independently of cAMP and PKA (88). Thus, there are multiple signaling avenues and target sites whereby GnRH could regulate β-catenin and expression of target genes such as Jun.
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PUTTING THE PIECES BACK TOGETHER
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β-Catenin has moved into the neighborhood of the GnRH transcriptional network. From all apparent appearances, β-catenin has established itself as a key player in enabling SF1 to act permissively in transducing the EGR1 signal from GnRH to Lhb in LβT2 cells (Fig. 4). Because Cga, Fshb, and Gnrhr also require permissive action of SF1 in responding to GnRH-induced changes in AP1, we predict that the orphan nuclear receptor will require similar enabling from β-catenin. Like SF1, TCF also needs β-catenin to exert a positive transcriptional effect on its target genes. Given the known TCF responsiveness of Jun in colon cancer cells, this IEG is an odds-on bet for serving as a natural GnRH-responsive target of TCF/β-catenin (Fig. 4). Although it is tempting to speculate that Atf3 may exhibit a similar dependency for TCF/β-catenin, it seems more likely that EGR1 will fill this need because Atf3 expression is known to fall under the influence of this zinc-finger DNA-binding protein (Fig. 4). Clearly, there is a growing need for uncovering new members of the GnRH transcriptional network. Part will come from recognition of new genes that are responsive to SF1 or TCF and dependent on β-catenin. There is also a need to decipher just how GnRH signals to β-catenin and whether coupling pathways are few and restricted or broad and promiscuous. Whatever the outcome, the GnRH transcriptional network is an interesting neighborhood worthy of repeated visitation and exploration.
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Fig. 4. Moving β-Catenin into the GnRH Transcriptional Network
β-Catenin enables SF1 to act permissively in transducing an EGR1 signal from GnRH to Lhb in gonadotropes. Because Cga, Fshb, and Gnrhr also require SF1 for GnRH responsiveness, we predict that regulated expression of these tertiary response genes will also require β-catenin. Transcriptional activity of Jun is highly sensitive to TCF/β-catenin interactions in cancer cells. Thus, GnRH responsiveness of Jun in gonadotropes will most likely depend on an interaction between TCF and β-catenin.
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FOOTNOTES
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Disclosure Statement: The authors have nothing to disclose.
First Published Online January 24, 2008
1 T.B.S. and A.K.B. contributed equally in the authorship and should be listed as co-first authors. 
Abbreviations: AP1, Activator protein 1; ATF3, activating transcription factor 3; AXIN, axin; CDC42, cell division cycle 42; EGR1, early growth response protein 1; GnRHR, GnRH receptor; GSK, glycogen synthase kinase; IEG, immediate early gene; JNK, JUN N-terminal kinase; LEF, lymphoid enhancer factor; PI3K, phosphatidylinositol 3-kinase; PITX1 or PITX2, paired-like homeodomain transcription factor 1 or 2; PKA, protein kinase A; PKC, protein kinase C; SF1, steroidogenic factor 1; SRC, c-src tyrosine kinase; TCF, T cell factor.
Received for publication November 16, 2007.
Accepted for publication January 17, 2008.
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