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Curr Opin Genet Dev. Author manuscript; available in PMC Aug 1, 2012.
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PMCID: PMC3134629

Sex Determination in Insects: a binary decision based on alternative splicing


The gene regulatory networks that control sex determination vary between species. Despite these differences, comparative studies in insects have found that alternative splicing is reiteratively used in evolution to control expression of the key sex determining genes. Sex determination is best understood in Drosophila where activation of the RNA binding protein encoding gene Sex-lethal is the central female-determining event. Sex-lethal serves as a genetic switch because once activated it controls its own expression by a positive feedback splicing mechanism. Sex fate choice in is also maintained by self-sustaining positive feedback splicing mechanisms in other dipteran and hymenopteran insects, although different RNA binding protein encoding genes function as the binary switch. Studies exploring the mechanisms of sex-specific splicing have revealed the extent to which sex determination is integrated with other developmental regulatory networks.


The gene regulatory networks that control sex determination vary tremendously between species and are among the most rapidly evolving networks in all of biology. In insects alone, marked variation exists in the primary chromosomal signals that determine sex (reviewed in [13]). For example, in some Diptera, such as Drosophila melanogaster, a chromosome counting mechanism is used: two X chromosomes signals female development and one X chromosome yields male development. In other Diptera, such as the distantly related housefly Musca domestica and the medfly Ceratitis capitata, the presence or absence of the Y chromosome determines sex. In Hymenoptera, such as the honeybee Apis mellifera and the wasp Nasonia vitripennis, sex is determined by a haplodiploid mechanism in which males emerge from unfertilized eggs and females from fertilized eggs. Despite this wide variety of initiating mechanisms, positive feedback alternative splicing loops have emerged as the key molecular strategy for maintaining sexual fate.

In this review I discuss the reiterative use of alternative splicing cascades to determine sex in insects. Since the Drosophila sex determination system is the gold standard to which other insects are compared, I will first review recent advances in our understanding of how Sex-lethal (Sxl) serves as the heritable switch gene by controlling its own splicing. I will then provide examples of how the RNA binding protein SXL renders the cell capable of initiating the cascade of post-transcriptional events that ultimately lead to sexual dimorphism. Lastly I will discuss the unexpected molecular parallels between the sex-determining positive feedback splicing mechanisms used by other insects where transformer (tra) occupies Sxl's position as the binary switch gene.

The sex fate choice decision in Drosophila: the Sxl autoregulatory splicing loop

In Drosophila melanogaster, the choice to be male or female is made early in embryogenesis when the X chromosome number is relayed through regulatory proteins such that Sxl is activated only in XX animals (reviewed in [4]). Despite its importance, the X counting mechanism functions only transiently and female identity is maintained by a self-sustaining positive feedback mechanism in which Sxl controls its own splicing. In the absence of SXL protein, as in XY cells, all Sxl transcripts include the translation-terminating third exon and a noncoding mRNA is produced. If SXL protein is present, as in XX cells, the third male-specific exon is skipped, thereby generating only protein-encoding mRNAs. Stable SXL expression is the pivotal female-determining event as it controls, either directly or indirectly, all aspects of sexual dimorphism.

Genetic studies have established that SXL protein is both necessary and sufficient to engage the Sxl autoregulatory splicing loop [5, 6]. The SXL protein contains two highly conserved RRM-type RNA binding domains. Accordingly, all of SXL's biological functions are believed to be the result of its ability to recognize and selectively bind to sequences with long poly(U) stretches interrupted by guanosines. The Sxl pre-mRNA contains several sets of putative SXL binding sets, the most critical of which are located in the introns >200 nucleotides downstream and >200 nucleotides upstream of the regulated male exon [7]. Although recognition of the appropriate binding site is essential, efficient exon skipping requires that SXL interacts with several general splicing factors, including the U1 snRNP (Table 1). Interestingly, when ChIP analysis was used to visualize the co-transcriptional recruitment of SXL and the U1 snRNP along the Sxl gene in female embryos, it was found that SXL does not interfere with the deposition of the U1 snRNP at the male exon 5' splice site [8••]. These data, together with earlier genetic and biochemical studies [911], support a model in which the spliceosome begins to assemble on the male exon in both males and females. In females, however, SXL prevents the reaction from finishing by interacting with and repressing the function of these general splicing factors. The reaction could be blocked immediately or spliceosome assembly could continue, stalling only later in the pathway. The end result is a dead-end complex that guarantees that the male exon is skipped, and that exon 2 is spliced to exon 4 (Figure 1).

Figure 1
Sxl splicing regulation in Drosophila
Table 1
General splicing factors required for Sxl male exon skipping

Although components of the spliceosome clearly play a direct role in SXL-mediated splicing inhibition, a recent study hints that communication between chromatin and RNA is also important [8••]. In this study, the Drosophila protein most closely related to the yeast histone H3K4me3 binding protein BYE1, called Protein Partner of Snf (PPS), was identified as part of the machinery required for Sxl male exon skipping. Consistent with its role in splicing, PPS interacts with the U1 snRNP, the SXL protein, and the Sxl pre-mRNA. Furthermore, ChIP studies indicate that PPS is likely to be loaded onto the Sxl RNA by the transcription machinery. Whether PPS is in fact associated with the transcription machinery and/or is a chromatin binding protein remains to be determined. However, in light of the well documented influence of chromatin structure and transcription on the pattern of alternative splicing (reviewed in [12]), it is tempting to speculate that PPS functions as an adaptor protein to ensure that the male exon is skipped, perhaps by accelerating the recruitment of SXL to the nascent transcript or by facilitating the formation of the inhibitory SXL/U1 snRNP interaction.

Although speculative, a mechanism integrating chromatin structure, transcription and splicing is likely to be especially important when the Sxl autoregulatory loop is first established in the early embryo (Figure 2). Engagement of the autoregulatory loop requires an initiating source of SXL protein and the coordinated regulation of two Sxl promoters: SxlPe (the establishment promoter) and SxlPm (the maintenance promoter). The first promoter to be activated, SxlPe, is transiently expressed during the syncytial blastoderm stage in response to two X-chromosomes. The SXL protein produced from the SxlPe derived transcripts is then present when SxlPm is first activated and serves to drive the initiating round of exon skipping. It is now clear that the changeover from SxlPe to SxlPm is precisely timed, and that disruptions in the chronology of these events interfere with the correct transmission of X-chromosome number to Sxl [13, 14•]. It would not be surprising if the machinery that controls the timing of SxlPm activation also participates in the decision to include or skip the male exon.

Figure 2
Regulatory logic that underlies stable SXL protein expression in XX Drosophila embryos

Once activated, Sxl is capable of initiating several different regulatory cascades leading to sexual dimorphism and dosage compensation. Although these regulatory cascades are traditionally viewed as unidirectional, recent genetic studies suggest that Sxl expression is subject to positive reinforcement from one of its immediate downstream target genes, transformer (tra) [15•]. Whether this effect is direct has not been tested, however the fact that TRA is an RNA binding protein and a tandem pair of TRA binding sites are found in the intron upstream of the male exon is suggestive of a direct effect. This retrograde splicing mechanism might stabilize and/or augment the decision to skip the third exon in females, thereby locking in the female-determining program.

Execution of the sex fate choice in Drosophila: Sxl-mediated gene regulation

The execution of all female-specific regulatory programs depend, directly or indirectly, on SXL protein expression (reviewed in [4, 16]). Two sets of recent studies emphasize the extent to which sex-specific splicing regulatory networks are intertwined with tissue-specific regulatory networks.

The gene regulatory network that leads to most, but not all, sexually dimorphic characteristics and behavior begins with SXL-directed tra splicing. Expression of the female specific RNA binding protein TRA in turn controls splicing of doublesex (dsx) and fruitless (fru) to produce sex-specific transcription factors that ultimately control most aspects of sexual differentiation and behavior. However, to say that the activity of dsx and fru is entirely controlled by the Sxltra pathway is a gross oversimplification, as dsx and fru are subject to an additional layer of highly restrictive tissue-specific transcriptional control [1720•]. Thus, even though ubiquitous SXL protein expression provides all cells with the “knowledge” that they are female, execution of the dsx/fru program is restricted to specific cell types by the availability of the pre-mRNA substrates for TRA-mediated splicing regulation.

A second example where tissue-specific and sex-specific regulation are integrated comes from studies showing that Sxl regulates Notch signaling to generate sexually dimorphic characteristics such as the number of neurosensory bristles on the A5 abdominal sternite [21]. In this case, SXL does not act through tra, but directly controls Notch by regulating its translation. Notch is used reiteratively during development to specify various cell fates, but most specification events are not sexually dimorphic. Therefore, it is likely that sex-specific Notch regulation is restricted to specific cell types, whereas the majority of Notch regulation is monomorphic. The mechanism that restricts sex-specific modulation of Notch signaling remains to be elucidated. Genetic studies carried out in the wing disc, however, suggest that Hrp48, a member of the hnRNP family of RNA binding proteins, is required to protect Notch mRNAs from SXL-mediated translational repression [22, 23]. Biochemical studies should clarify whether Hrp48 acts on the Notch mRNA substrate to restrict its availability for SXL-mediated regulation or whether Hrp48 influences SXL activity directly.

Shared regulatory logic amid evolutionary diversity

Starting with Drosophila melanogaster as the source of comparative information, molecular phylogenetic studies have revealed both evolutionary conservation and divergence among the regulatory pathways that control sex in insects. For example, divergence at the top of the pathway is evident, as Sxl's sex-specific expression pattern and function extends only to its closest sibling species [24, 25]. The sex-specific splicing regulation of dsx and fru, on the other hand, is highly conserved in a broad range of insects (reviewed in [26, 27]). Strikingly, there is a high degree of conservation in sequence elements located in and around the regulated splice sites that include putative TRA binding sites. This suggests that the evolutionary conservation extends to the molecular mechanism that controls dsx and fru splice site usage. Together with RNAi knockdown experiments that demonstrate functional conservation across a diverse sampling of insects, these phylogenetic studies suggest an ancient origin and role for dsx and fru in sex determination.

Despite the fact that dsx and fru homologs contain conserved sets of TRA binding sites, the TRA protein itself is poorly conserved. Indeed, TRA has been labeled as one of the more rapidly evolving members of the SR family of RNA binding proteins (see for example Figure S2 in [28••]). The lack of sequence conservation while retaining RNA binding specificity can be explained by the co-evolution between TRA and its putative binding partner TRA-2. In Drosophila TRA function requires an interaction with the non-sex specific TRA-2 RNA binding protein. While it is not known whether TRA-2 is an obligate binding partner in other insects, a conserved role for TRA-2 in sex specific splicing is supported by the observation that tra-2 homologs are required for dsx and fru splicing [2931].

A role for tra as the sex-determination switch gene was first suggested by studies in the medfly Ceratitis capitata where Cctra was found to be required for its own splicing [30, 32, 33]. Interestingly, the tra genomic structure differs considerably between Drosophila and Ceratitis. In fact, the Cctra architecture is more similar to that of Sxl, with translation terminating male-specific exons that are sex-specifically skipped to produce protein encoding mRNAs (Figure 3). tra homologs have also been identified as the sex switch gene in a number of other insects, including the distantly related housefly Musca domestica, honeybee Apis mellifera and wasp Nasonia vitripennis [28••, 34••, 35, 36]. In each case translation-terminating male exons form the backbone of an autoregulatory splicing mechanism for maintaining sexual fate (Figure 3). The recurrence of exon skipping in this context leads us to speculate that alternative splicing control is an evolutionarily advantageous strategy for positive feedback regulatory mechanisms.

Figure 3
Phylogenetic comparison of tra gene structure and regulation

The central unanswered question with regard to cell fate determination is how the decision whether or not to activate the positive feedback splicing loop is made. In both the medfly and the housefly, it is the presence or absence of the Y chromosome that determines sex, not X-chromosome number. This implies that there is both a Y-encoded product that prevents the initiation of the tra autoregulatory loop in males and a mechanism that provides the initiating source of TRA protein in females. The presence of maternally provided tra mRNA in both male and female embryos, suggests that an initiating source of TRA protein is maternally provided to all embryos and that male development depends on a Y-encoded mechanism that interferes with establishment of the autoregulatory loop [28••, 37].

In Hymenoptera, such as the honeybee Apis mellifera and the wasp Nasonia vitripennis, sex is determined by a haplodiploid mechanism in which males emerge from unfertilized eggs and females from fertilized eggs. Recent studies in the wasp have shown that while maternal tra mRNA is likely to provide an initiating source of TRA protein to both haploid and diploid embryos, zygotic tra pre-mRNA transcription is limited to diploid embryos [34••]. Haploid embryos are therefore deprived of pre-mRNA substrate during this critical period of development and the splicing loop is not engaged. Although the mechanism that restricts tra transcription to diploids remains to be discovered, genomic imprinting is a potential explanation as it mediates many parent of origin effects.

Concluding Remarks

Together these comparative studies illustrate that positive feedback splicing mechanisms are used reiteratively in evolution to maintain sexual fate. Future studies focused on the similarities and differences in how self-regulation is accomplished and how downstream target gene expression is modulated will expand our understanding of the organization, function and evolution of the RNA splicing network that controls sex determination. It will be particularly interesting to determine how much variability is tolerated while equivalent homologous functions are still maintained in evolution. In addition, much remains to be learned about how the self-regulating binary switch genes are activated in early embryogenesis. In all insects examined thus far, including Drosophila, activation of the autoregulatory splicing loop is tightly correlated with the events leading to formation of the cellular blastoderm and the maternal to zygotic transition. Achieving a deeper understanding of how sex-specific splicing regulation is connected to the more general regulatory events occurring during this dynamic period of development will be a challenge for the field in the coming years.


I thank Hua Lou and members of my laboratory for helpful comments on the manuscript, and I apologize to my colleagues whose work I did not cover due to space constraints. My work on Sxl regulation and function is funded by a grant from The National Institutes of Health.


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