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Development. Dec 1, 2009; 136(23): 3881–3887.
PMCID: PMC2778738

xol-1, the master sex-switch gene in C. elegans, is a transcriptional target of the terminal sex-determining factor TRA-1

Abstract

In the nematode Caenorhabditis elegans, sex is determined by the ratio of X chromosomes to sets of autosomes: XX animals (2X:2A=1.0) develop as hermaphrodites and XO animals (1X:2A=0.5) develop as males. TRA-1, the worm ortholog of Drosophila Cubitus interruptus and mammalian Gli (Glioma-associated homolog) proteins, is the terminal transcription factor of the C. elegans sex-determination pathway, which specifies hermaphrodite fate by repressing male-specific genes. Here we identify a consensus TRA-1 binding site in the regulatory region of xol-1, the master switch gene controlling sex determination and dosage compensation. xol-1 is normally expressed in males, where it promotes male development and prevents dosage compensation. We show that TRA-1 binds to the consensus site in the xol-1 promoter in vitro and inhibits the expression of xol-1 in XX animals in vivo. Furthermore, inactivation of tra-1 enhances, whereas hyperactivation of tra-1 suppresses, lethality in animals with elevated xol-1 activity. These data imply the existence of a regulatory feedback loop within the C. elegans sex-determination and dosage-compensation cascade that ensures the accurate dose of X-linked genes in cells destined to adopt hermaphrodite fate.

Keywords: Sex determination, Dosage compensation, Caenorhabditis elegans, TRA-1/Gli/Ci, xol-1, Chromatin

INTRODUCTION

The primary signal that determines sexual differentiation in C. elegans is the ratio of sex chromosomes to sets of autosomes: diploid animals with two X chromosomes (XX) are hermaphrodites and animals with one X chromosome (XO) are males (Meyer, 2005; Zarkower, 2006). All aspects of somatic sexual fate in this organism are controlled by the sex-determination and dosage-compensation pathway, which comprises a cascade of negative regulatory interactions (Fig. 1A). Upstream in this pathway, the X-chromosome-counting mechanism culminates in switching xol-1 (XO lethal) on in males and off in hermaphrodites (Meyer, 2005; Zarkower, 2006). The activity of xol-1 is determined by dose-sensitive signals from both the X chromosome and autosomes. X-signal elements (XSEs), including fox-1 (feminizing gene on X), sex-1 (signal element on X) and sex-2, repress xol-1. By contrast, autosomal signal elements (ASEs), including sea-1 (signal element on autosome), sea-2 and sea-3, promote xol-1 activity. In XO animals, the inhibitory effects of XSEs on xol-1 are not sufficient to overcome the stimulatory effects of ASEs, thereby rendering xol-1 active. In XX animals, the combined dose of XSEs is able to repress xol-1.

Fig. 1.
xol-1 is a transcriptional target of TRA-1A. (A) The C. elegans sex-determination and dosage-compensation pathway. xol-1 is controlled by X-chromosome and autosomal signal elements (XSEs and ASEs). tra-1 is the terminal regulator of somatic sexual fate. ...

XOL-1 inhibits the sdc (sex-determination and dosage-compensation defect) genes sdc-1, sdc-2 and sdc-3, which in turn regulate both somatic sex determination and X-chromosome dosage compensation (Meyer, 2005). In the sex-determination pathway, the SDC proteins downregulate the autosomal gene her-1 (hermaphroditization of XO animals) (Trent et al., 1991; Dawes et al., 1999; Chu et al., 2002). her-1 encodes a secreted protein that binds to and inhibits the transmembrane receptor product of tra-2 (sexual transformer) (Hodgkin, 1980). When TRA-2 function is off, the FEM (feminization of XO and XX animals) proteins FEM-1, FEM-2 and FEM-3, together with CUL-2 (Cullin-2-like ubiquitin ligase), form a complex to target the zinc-finger transcription factor TRA-1A for proteasome-mediated degradation (Starostina et al., 2007). In the absence of functional TRA-1A, male-specific genes can be transcribed. When the SDCs are inactive, HER-1 is able to block TRA-2. As a result, the inactive FEM-1/2/3-CUL-2 complex allows TRA-1A to be cleaved C-terminally, and to thereby become resistant to proteasomal degradation. In turn, TRA-1A represses male-specific genes (Zarkower, 2006). Thus, tra-1 functions as the terminal control gene of the nematode sex-determination pathway.

The SDC proteins also constitute components of the worm dosage-compensation complex (DCC), which ensures that X-linked genes are expressed at similar levels in both sexes (Chuang et al., 1996; Lieb et al., 1996; Lieb et al., 1998; Meyer, 2005). In addition to the SDCs, this complex contains other proteins, including MIX-1 (mitosis and X-associated), DPY-21 (Dumpy), DPY-26, DPY-27, DPY-28, CAPG-1 (CAP-G subunit of condensin I) and DPY-30 (Meyer, 2005; Csankovszki et al., 2009) (see Fig. 1A). Interestingly, dosage-compensation proteins establish both gene-specific (her-1) and chromosome-wide (i.e. X-specific) transcriptional repression (Chu et al., 2002). The DCC is recruited to specific recognition elements on hermaphrodite X chromosomes, then spreads to the rest of the chromosome to reduce gene expression by half (Csankovszki et al., 2004; McDonel et al., 2006; Jans et al., 2009).

In this study, we report a novel feedback mechanism that controls dosage compensation through repressing xol-1. We show that xol-1 is a direct molecular target of TRA-1A repression. Inactivation of tra-1 causes ectopic expression of xol-1 in XX embryos. This suggests that the XSEs alone are not sufficient to fully repress xol-1. Moreover, decreased activity of tra-1 enhances, whereas its increased activity suppresses, lethality in animals with elevated xol-1 activity. Thus, tra-1 contributes to the maintenance of xol-1 repression, and indirectly to halving the expression of X-linked genes in cells destined to adopt hermaphrodite fate.

MATERIALS AND METHODS

Nematode strains and alleles

The wild-type C. elegans strain corresponds to var. Bristol (N2). The following mutant strains were used: CB2823 tra-1(e1488)III; eDp6(III;f); CB2590 tra-1(e1099)/dpy-18(e1096)III; CB3844 fem-3(e2006)IV; NG41 sex-1(gm41)X; TY2384 sex-1(y263)X; CB428 dpy-21(e428)V; TY2431 him-8(e1487)IV; xol-1::gfp(yIs34)V; CB1489 him-8(e1489)IV; CB4088 him-5(e1490)V; BU099 hbEx2[mut pxol-1::gfp + unc-119(+) + rol-6(su1006)]; TY1807 xol-1(y9)X; CB3769 tra-1(e1575gf)/+III; tra-3(e1767)IV; DH1033 sqt(sc103)II; bIs1[VIT-2::GFP + rol-6(su1006)]X; and CB678 lon-2(e678)X.

Gel mobility shift assay

TRA-1A protein was generated by in vitro transcription and translation of full-length tra-1 cDNA from pDZ118 (kindly provided by David Zarkower, University of Minnesota, Minneapolis, MN, USA), using a T7-based coupled reticulocyte lysate system (TNT Coupled Reticulocyte Lysate System, Promega). After in vitro translation, ZnSO4 was added to 50 μM. For preparing DNA probes, single-stranded oligonucleotides were annealed in TE (10 mM Tris-Cl, 1 mM EDTA, pH 7.6) and labeled by filling in the single-stranded termini with Klenow polymerase in the presence of [α32P]dCTP according to standard procedures. The following oligonucleotides were used:

wt xol-1 L 5′-GGGGCCCCTGTAAGACCACACACGACGAAAACCTCTTGTT-3′ and R 5′-GGGGAACAAGAGGTTTTCGTCGTGTGTGGTCTTACAGGGG-3′;

mut xol-1 L 5′-GGGGGCCCCTGTAACGGTACACACGACGAAAACCTCTTGTT-3′ and R 5′-GGGGGAACAAGAGGTTTTCGTCGTGTGTACCGTTACAGGGG-3′;

wt mab-3 L 5′-GGGGGCGTTCTCTAATTATCGTCGTGTGAGGTCTTCTAT-3′ and R 5′-GGGGGATAGAAGACCTCACACGACGATAATTAGAGAACG-3′.

Experiments were performed essentially as described previously (Yi et al., 2000). Briefly, probes of 40,000 cpm (~1 ng DNA) were incubated for 20 minutes on ice in the presence of 3 μl protein before electrophoresis on 4% polyacrylamide 0.5× TBE gels at 160 V at room temperature. The gels were dried and exposed to Kodak XAR film.

RNA interference and transgene construction

Total RNA was isolated from mix-staged wild-type worms, and specific cDNA fragments were amplified by RT-PCR. The following forward and reverse primers were used:

tra-1, 5′-CTAGCTAGCTAGACAATCCGGAGCATCTCAAG-3′ and 5′-GGGGTACCCCTGATGATGTTGAGCCAGAGC-3′;

xol-1, 5′-CATGCCATGGCATGGCGCGAAAACAGTCCAGTC-3′ and 5′-CATGCCATGGCATGGCCGTCGTCGAAAAATGAG-3′;

sea-2, 5′-CATGCCATGGCATGCGGAAAGCTCCTCAACTCTG-3′ and 5′-CATGCCATGGCATGACCGTCACGAATGAGGTTTC-3′.

The amplified fragments were cloned into pGEM-T Easy (Promega) and subcloned into pPD129.36. The resulting constructs were transformed into E. coli HT115(DE3). RNA interference (RNAi) experiments were performed at 25°C. To generate a xol-1::gfp reporter lacking the putative TRA-1A binding site (pmutxol-1::gfp), two genomic fragments were amplified using the following forward and reverse primer pairs:

Forw1 5′-AAGGCGCGCCTTGCAGAACAGCTTTGATCG-3′ and Rev1 5′-TGTTGACCGTTACAGGGGTATTCGCGGGCGTTTGAAAATAGTG-3′;

Forw2 5′-CGAATACCCCTGTAACGGTCAACACGACGAAAACCTCTTGTTCC-3′ and Rev2 5′-TTGCGGCCGCAAGGACCCTGCAACAAAACG-3′.

A single fragment was generated by fusion PCR, digested with AscI and NotI, and cloned into pRH21. Extrachromosomal array-bearing animals were examined in wild-type and him-5 mutant backgrounds.

RESULTS AND DISCUSSION

TRA-1A binds to the regulatory region of xol-1

The transcriptional regulator tra-1 encodes two proteins: TRA-1A with five zinc-finger motifs and TRA-1B with two zinc fingers (Zarkower and Hodgkin, 1992). TRA-1A has a DNA-binding ability, whereas TRA-1B does not (Zarkower and Hodgkin, 1993). Until now, only a few direct targets of TRA-1A have been identified, including egl-1 (egg-laying defective), mab-3 (male abnormal), ceh-30 (C. elegans homeobox), fog-1 (feminization of germline), fog-3 and dmd-3 (DM-domain family) (Conradt and Horvitz, 1999; Yi et al., 2000; Schwartz and Horvitz, 2007; Peden et al., 2007; Mason et al., 2008). These TRA-1A targets, all of which are repressed in XX animals, determine different aspects of sexual fate determination.

The availability of sequence information of TRA-1 binding sites in the regulatory regions of known targets prompted us to deduce a consensus binding site from the nucleotides conserved within these sites (Fig. 1B). We found that nine of the 18 bases in TRA-1A binding sites are strictly conserved, and three bases change only once. We then searched the C. elegans genome for consensus TRA-1A binding sites, considering the highly conserved nucleotides at their appropriate positions (TTATTCNNNNTGTGGATGGTC). Our analysis identified 35 novel putative TRA-1A binding sites within upstream regulatory or intronic sequences. One of these sites is located within the xol-1 promoter, 154 bp upstream of the ATG translational initiation site (Fig. 1C). This consensus site, which is almost identical to that found in the mab-3 regulatory region, is highly conserved in Caenorhabditis species, and, interestingly, is repeated three times in the C. remanei xol-1 genomic environment (Fig. 1D).

We next assessed whether in-vitro-translated full-length TRA-1A is able to bind to an oligonucleotide corresponding to this consensus site in the xol-1 promoter. Using gel electrophoretic mobility shift assays, we detected efficient binding of TRA-1A to this element (Fig. 1E). By contrast, TRA-1A was not able to bind to the oligonucleotide when the putative TRA-1A binding site was mutated in four crucial positions (see Materials and methods). In addition, unlabeled wild-type, but not mutant, xol-1 oligonucleotide was able to compete with the labeled oligonucleotide in a concentration-dependent manner (Fig. 1E). We conclude that TRA-1A is able to bind to the consensus site in the xol-1 promoter in vitro.

TRA-1 represses xol-1 in XX animals

xol-1 promotes the male mode of dosage compensation and sexual fate determination. Normally, xol-1 is expressed in XO embryos to repress the SDC proteins. Therefore, XOL-1 prevents the DCC from undergoing assembly, causing the her-1 autosomal locus and the single male X chromosome to remain transcriptionally fully active. In XX animals, xol-1 is repressed and unable to inhibit the SDCs. To monitor xol-1 expression, we analyzed the expression of an integrated xol-1::gfp transcriptional fusion reporter, yIs34 (Dawes et al., 1999). Consistent with previous results (Carmi et al., 1998), xol-1::gfp was inactive in a wild-type background and was expressed in XO, but repressed in XX, embryos in the him-8(e1489) (high incidence of males) mutant background (Fig. 2A,B). The nuclear hormone receptor SEX-1 acts as an X-chromosome-specific signal to downregulate xol-1 transcription (Carmi et al., 1998). Consistently, yIs34 was ectopically expressed in sex-1(gm41) mutant XX embryos (Fig. 2C). A significant proportion of sex-1 mutant embryos was arrested in development, probably owing to xol-1 misregulation (see below).

Fig. 2.
tra-1 contributes to xol-1 repression in XX animals. (A) xol-1 is not active in wild-type XX animals. An integrated xol-1::gfp reporter (yIs34) is not expressed in wild-type embryos of XX karyotype. (B) Expression of yIs34 in a him-8(e1489) mutant genetic ...

We monitored xol-1::gfp expression in tra-1(e1488) mutant animals. e1488 is a reduction-of-function mutation that confers an intersex phenotype to animals of XX karyotype. Homozygous tra-1(e1488) mutants have a hermaphrodite gonad and intestine, but the rest of their body (e.g. the tail region, musculature and nervous system) is masculinized (Hodgkin, 1993). We found that at certain developmental stages xol-1::gfp was expressed in tra-1(e1488) mutant XX embryos (Fig. 2D). This implies that TRA-1A represses xol-1 in animals of hermaphrodite karyotype. To confirm these results, we also examined xol-1::gfp expression in tra-1(e1099) mutant animals. e1099 is a strong loss-of-function allele that transforms XX animals into low-fertility males. Similar to what we observed in the hypomorph tra-1 mutant background, the xol-1::gfp reporter was ectopically active in a proportion of the progeny of tra-1(+/e1099) heterozygous hermaphrodites, which we infer to be homozygous for tra-1(e1099) (Fig. 2E). Furthermore, we depleted TRA-1 by RNA interference (RNAi) and examined the effect of this treatment on xol-1 expression. tra-1 RNAi (see Szabó et al., 2009) strongly phenocopied tra-1(e1488): tra-1(RNAi) animals were intersexes, i.e. they developed both vulval structure and male tail at almost full penetrance. xol-1 activity was obvious in embryos produced by XX animals treated with tra-1 double-stranded RNA (Fig. 2F). Finally, we generated worms carrying extrachromosomal arrays containing a modified form of the xol-1::gfp reporter [Ex(pmutxol-1::gfp)], in which the putative TRA-1A binding site is mutated. A proportion of the progeny of these worms, assumed to be the array-bearing XX embryos, were green (Fig. 2G). Together, these results indicate that TRA-1A binds to the consensus site in the xol-1 promoter and inhibits expression.

Inactivation of tra-1 enhances, whereas hyperactivation of tra-1 suppresses, lethality in animals with elevated xol-1 activity

Inactivation of the XSE sex-1 causes greater than 30% embryonic lethality in XX animals, presumably owing to ectopic xol-1 expression (Nicoll et al., 1997; Carmi et al., 1998) (Table 1). Inactivating another xol-1 repressor, such as tra-1, would be expected to enhance this lethality. To test this, we first quantified lethality in mutant animals defective for tra-1. At 25°C, 41.4% and 47.9% of tra-1(e1488) and tra-1(e1099) loss-of-function mutant embryos failed to develop to adulthood, respectively (Table 1). These values are comparable to, or even higher than, those obtained in sex-1(gm41) and sex-1(y263) mutant animals maintained under identical conditions. Then, we generated sex-1(-); tra-1(-) double mutants. Lethality detected in either single mutant appeared to be additive in the corresponding sex-1(-); tra-1(-) double-mutant animals. This suggests that sex-1 and tra-1 repress xol-1 via parallel mechanisms.

Table 1.
tra-1 activity influences the penetrance of lethality in sex-1 and dpy-21 loss-of-function mutants

To test whether an increase in tra-1 activity can suppress sex-1 lethality, we also generated sex-1(-); fem-3(-) double-mutant nematodes and scored them for viability. fem-3 inhibits the activity of tra-1 in the sex-determination pathway (Fig. 1A). Loss-of-function mutations in fem-3, similarly to tra-1 gain-of-function mutations, feminize both XX and XO animals (i.e. fem-3-deficient and tra-1-hyperactive animals produce only oocytes). The fem-3(e2006) mutation significantly increased viability in the sex-1 mutant background (Table 1). Thus, hyperactivation of tra-1 is able to suppress lethality in XX animals with derepressed xol-1. Consistent with these data, the tra-1 gain-of-function mutation e1575 markedly suppressed embryonic lethality in sex-1(gm41) mutant animals (Table 1). It is worth noting that fem-3(e2006) single-mutant animals also exhibited a significant degree of embryonic lethality (Table 1). This was unexpected because xol-1 is normally repressed in XX animals, and thereby downregulation of fem-3, if it acts through tra-1, should not influence xol-1 activity in the soma. Since tra-1(e1575gf) led to only modest embryonic lethality (Table 1), fem-3 probably has a function that is required for viability and independent of sex determination. Because inhibiting other components of the sex-determination pathway similarly caused developmental arrest with moderate penetrance [at 20°C: fem-2(b245) mutants, 4.8% lethality (n=126); her-1(e1518) mutants, 5.1% (n=147)], the observed lethality might be a general property of the pathway.

XOL-1 functions to inhibit dosage compensation (Meyer, 2005). Consistent with the potential role of tra-1 in controlling xol-1, insufficient TRA-1 levels enhanced lethality in dpy-21(e428) mutant nematodes, in which the DCC is already compromised (Table 1). Together, these data indicate that tra-1 modulates the activity of xol-1, which regulates both sex determination and dosage compensation.

Lethality of tra-1 mutant embryos depends on xol-1 activity

As shown above, a significant proportion of tra-1-deficient, but not of tra-1(e1575gf) mutant, XX animals die at different stages of development (Table 1). Therefore, we tested whether the lethality of tra-1 mutant embryos was a result of xol-1 overexpression. If it were, repressing xol-1 should enhance the viability of tra-1 loss-of-function mutants. Embryonic lethality was compared for tra-1 mutants treated with xol-1 versus control double-stranded RNA (Fig. 3A). Although xol-1 RNAi treatment is likely to deplete XOL-1 only partially [as most xol-1(RNAi) XO embryos were able to develop into adults; data not shown], it did significantly decrease the percentage of dead embryos in both sex-1 (control) and tra-1 mutant backgrounds. For example, embryonic lethality in the tra-1(e1099) mutant background was reduced by half with xol-1 RNAi (Fig. 3A). Similarly, the xol-1(y9) mutation markedly enhanced viability in tra-1(-) mutant embryos (Fig. 3B). Depletion of the ASE SEA-2 (which normally activates xol-1) also caused a significant suppression of lethality in tra-1(e1099) mutant animals (Fig. 3B). These results indicate that lethality caused by tra-1 deficiency is, at least partially, xol-1 dependent.

Fig. 3.
Lethality in tra-1-deficient animals depends on increased xol-1 activity. (A) Lethality in tra-1 mutants is suppressed by depletion of XOL-1. Control animals were fed E. coli HT115 expressing the empty vector alone and were maintained under inducing conditions. ...

To address whether lethality caused by tra-1 deficiency is XX specific, we scored the ratio of males in him-8(e1489) mutant animals depleted for tra-1. Indeed, the percentage of males was increased in him-8(e1489); tra-1(RNAi) animals (46.9% males, n=168), as compared with him-8(e1489) mutants treated with control RNAi (35.7% males, n=145). To directly determine the sex of arrested embryos, we used an integrated X-linked GFP reporter, bIs1 (Grant and Hirsh, 1999). lon-2(e678)X hermaphrodites were treated with tra-1 double-stranded RNA from the L2 larval stage, then mated with males carrying bIs1. The arrested F1 progeny were tested for the presence of gfp by PCR. Sixteen out of the 20 embryos tested were gfp positive (XX karyotype), indicating that XX embryos are overrepresented in the arrested population.

TRA-1A is similar to Drosophila Cubitus interruptus and to vertebrate Glioma-associated homolog proteins (Zarkower and Hodgkin, 1992). Members of this protein family act as the terminal transcription factors of the Hedgehog (Hh) signaling pathway and control several key developmental processes in both invertebrates and vertebrates. In humans, dysregulated Hh signaling has been implicated in cancer, skeletal malformation and defective neuronal patterning. Studies of tra-1 in nematodes might therefore shed light on the role of Hh signaling in human development and disease.

tra-1 has been shown to interact with the class B synMuv (synthetic Multivulva) pathway: it cooperates with the synMuv B gene tra-4 to promote female development (Grote and Conradt, 2006), represses vulval induction in a synMuv A mutant background (Szabó et al., 2009), and appears to directly regulate the expression of the Hox gene lin-39 (Szabó et al., 2009), a central regulator of vulval development (Takács-Vellai et al., 2007). The synMuv B pathway includes chromatin remodeling factors, such as members of the NuRD nucleosome remodeling and histone deacetylase complex and the Rb (Retinoblastoma)/E2F complex (Harrison et al., 2006). It is therefore likely that xol-1 repression by TRA-1A involves changes in chromatin structure.

In C. elegans, both dosage compensation and sex determination are thought to be irreversibly determined early in life by the X:A ratio, which renders the master sex-switch gene xol-1 to be active or inactive (Meyer, 2005; Zarkower, 2006). In XX animals, the combined dose of XSEs represses xol-1, allowing the DCC to assemble and repress the autosomal gene her-1 and halve the expression from both X chromosomes. However, following X-chromosome repression, the expression of XSEs is also reduced by half (Gladden et al., 2007). It is possible that repression of the XSEs necessitates an additional mechanism to maintain xol-1 repression. In this study, we have shown that TRA-1A, the terminal transcription factor of the C. elegans sex-determination pathway, also represses xol-1, the upstream regulator of the pathway (Fig. 3C). Since the other known autosomal regulators of xol-1, the ASEs, promote xol-1 expression, tra-1 is the first autosomal gene identified as inhibiting xol-1. Our study shows that the role of TRA-1A in hermaphrodites is to repress male-specific genes at two levels. TRA-1A not only represses the terminal male sexual differentiation genes, but also xol-1, the male-specific upstream regulator of the pathway. By repressing xol-1 in XX animals, TRA-1A indirectly contributes to the maintenance of X-chromosome repression during dosage compensation. Understanding the mechanism by which X-chromosome repression is maintained throughout the lifetime of hermaphrodites is an important area of research (Meyer, 2005). Our results might help to better understand the molecular mechanism underlying X-linked gene dosage equalization between hermaphrodites and males.

Acknowledgements

We thank David Zarkower for the tra-1 cDNA clone; the Caenorhabditis Genetics Center funded by the NIH for nematode strains; and Martha Snyder for critical reading of the manuscript. This work was supported by grants from the OTKA Hungarian Scientific Research Funds K68372 to T.V. and PD75477 to K.T-V, from the National Office for Research and Technology (TECH_08_A1/2-2008-0106) to T.V, and by the NIH grant (NIH RO1 GM079533) to G.C. T.V. and K.T.-V. are grantees of the János Bolyai Scholarship. Deposited in PMC for release after 12 months.

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