For 600 million years, the two best-understood metazoan species, the nematode Caenorhabditis elegans and fruit fly Drosophila melanogaster, have developed independent strategies for solving a biological problem faced by essentially all metazoans: how to generate two sexes in the proper proportions. The genetic program for sexual dimorphism has been a major focus of research in these two organisms almost from the moment they were chosen for study, and it may now be the best-understood general aspect of their development. In this review, we compare and contrast the strategies used for sex determination (including dosage compensation) between "the fly" and "the worm" and the way this understanding has come about. Although no overlap has been found among the molecules used by flies and worms to achieve sex determination, striking similarities have been found in the genetic strategies used by these two species to differentiate their sexes.

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The Drosophila sex-determination switch gene Sex-lethal (Sxl) and the X-chromosome signal element genes (XSEs) that induce the female-specific expression of Sxl are transcribed extremely early in development when most of the genome of this organism is still silent. The DNA sequence CAGGTAG had been implicated in this pre-cellular blastoderm activation of sex-determination genes. A genome-wide computational search, reported here, suggested that CAGGTAG is not specific to early sex-determination genes, since it is over-represented upstream of most genes that are transcribed pre-cellular blastoderm, not just those involved in sex determination. The same search identified similarly over-represented, one-base-pair degenerate sequences as possible functional synonyms of CAGGTAG. We call these heptamers collectively, the TAGteam. Relevance of the TAGteam sequences to pre-cellular blastoderm transcription was established through analysis of TAGteam changes in Sxl, scute (an XSE), and the 'ventral repression element' of the pattern-formation gene zerknüllt. Decreasing the number of TAGteam sites retarded the onset of pre-blastoderm transcription, whereas increasing their number correlated with an advanced onset. Titration of repressors was thought to be the rate-limiting step determining the onset of such early transcription, but this TAGteam dose effect shows that activators must also play an important role in the timing of pre-blastoderm gene expression.

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The binary switch gene Sex-lethal (Sxl) must be on in females and off in males to allow the proper elaboration of the appropriate sexual developmental pathway in Drosophila melanogaster. Previous studies suggested a mechanism in which the on/off regulation of Sxl occurs post-transcriptionally at the level of RNA splicing. A critical prediction of this model is that functional Sx/proteins are absent in males but present in females. In this report we show that the expected full-length proteins are only present in female animals. Multiple forms of Sxl protein are found in females, some of which are expressed in a stage-and tissue-specific pattern. Consistent with a role of Sxl proteins in regulating alternate splicing, the proteins are localized in the nucleus where they exhibit a punctate staining pattern. Surprisingly, several minor Sxl proteins appear to be present in specific tissues of both sexes of adults. The possible origin of these species is discussed. We also show that Sx/ expression in the early embryo is sex specific and depends on maternal daughterless and zygotic sisterless-b activity in accordance with the established roles of these genes as positive regulators of Sxl. The onset of Sx/ expression in the germ line occurs later than that in the soma.

Sexual identity in Drosophila is determined by zygotic X-chromosome dose. Two potent indicators of X-chromosome dose are sisterless-a (sis-a) and sisterless-b (sis-b). Genetic analysis has shown that a diplo-X dose of these genes activates their regulatory target, the feminizing switch gene Sex-lethal (Sxl), whereas a haplo-X dose leaves Sx/inactive. sis-b encodes a transcriptional activator of the bHLH family that dimerizes with several other HLH proteins required for the proper assessment of X dose. Here, we report that sis-a encodes a bZIP protein homolog that functions in all somatic nuclei to activate Sx/transcription. In contrast with other elements of the sex-determination signal, the functioning of this transcription factor in somatic cells may be specific to X-chromosome counting. Using in situ hybridization, we determined the time course of sis-a, sis-b, and Sx/transcription during the first few hours after fertilization. The pattern of sis-a RNA accumulation is very similar to that for sis-b, with a peak in nuclear cycle 12 at about the time of onset of Sx/ transcription. Considered in the context of other studies, these results suggest that the ability to distinguish one X from two is attributable to combinatorial interactions between bZIP and bHLH proteins and their target, Sx/, as well as to positive and negative interactions with maternally supplied and zygotically produced proteins.