The somatic sex hierarchy. A single multi-branched regulatory hierarchy controls all somatic sexual differences in Drosophila melanogaster (Figure 1). The three branches of the hierarchy govern (1) X chromosome dosage compensation, (2) somatic sexual differentiation, and (3) male sexual behavior.
The initial steps in sex determination regulatory hierarchy assess the X chromosome: Autosome (X:A) ratio and establish sex by setting the activity of Sex lethal (Sxl) to "on-produces and SXL protein" in females (XX flies) and "off-does not produce a protein" in males (XY flies). In females SXL protein turns off dosage compensation by preventing the translation of the mRNA from the male-specific lethal-2 (msl-2) gene which is required for dosage compensation. In males, where there is no SXL protein, the msl-2 mRNA is translated and dosage compensation occurs. In addition, the presence (in females) or absence (in males) of SXL triggers cascades of sex-specific alternative mRNA splicing events that lead to the production of sex-specific doublesex (dsx) and fruitless (fru) products (Figure 2).
In the case of dsx both the male- and female-specific dsx mRNAs encode sex-specific zinc finger proteins (DSXM and DSXF, respectively), which have identical DNA binding domains, but different carboxy termini. The dsx gene is the last sex determination regulatory gene in its branch of the hierarchy.
In the case of fru only the products of the P1 fru promoter are expressed sex-specifically as part of the sex determination hierarchy. Transcripts from the P1 fru promoter are sex-specifically spliced in females, like dsx, under the direct control of the TRA and TRA-2 proteins. In males, which lack TRA protein, a default splice occurs. Conceptual translation of the P1 derived fru mRNAs reveals that they encode proteins with a BTB domain at their amino termini and one of three alternative Zn-finger pairs at their carboxy termini. The P1-derived male-specific mRNAs encode proteins that differ from those predicted from the female mRNAs by the presence of 101 amino acids N-terminal to the BTB domain. Immunohistochemistry revealed that the male-specific P1 mRNAs are translated; whereas the P1-derived female-specific mRNAs are not translated. We proposed that it is these male-specific FRU proteins that function to establish the potential for male courtship behavior .
With respect to the processes controlled by the dsx vs. fru
branches of the hierarchy we know the following. The dsx branch
is responsible for all aspects of somatic sexual differentiation outside
of the CNS. Thus
dsx governs sexual dimorphism in features of external
morphology such as pigmentation, sex-specific aspects of abdominal segmentation,
and bristle patterns, as well as all the structures that comprise the internal
and external genitalia. Wild-type dsx function is also required
for internal biochemical differences that distinguish the somatic cells
of the two sexes. In addition, wild-type dsx function is required
for several aspects of sexual differentiation that may, or do, have behavioral
consequences. These include (1) the sex-specific division patterns of a
set of neuroblasts found in the abdominal ganglion of both sexes, (2) the
sex-specific patterns of pheromones, (3) the production of courtship-specific
humming sounds, and (4) female courtship behavior.
Figure 1. The regulatory hierarchy controlling somatic sexual differences in Drosophila melanogaster.The fru branch of the somatic sex determination hierarchy is necessary for all, or nearly all, steps of male courtship behavior. Wild-type fru function is also required for the differentiation of a male-specific abdominal muscle, termed the Muscle of Lawrence (MOL). It is the sex of the innervating motorneurons, rather than the sex of the muscle cells, that determine whether a MOL will form. Since both the MOL and male courtship phenotypes are determined by the genotype of the CNS, this suggested that the function of the fru branch of the sex hierarchy is to control aspects of differentiation in the CNS. This hypothesis is strongly supported by the finding that the P1 derived male-specific FRU proteins are expressed almost exclusively in a limited number of CNS cells.
Figure 2. Sex-specific splicing patterns of pre-mRNAs from sex determination regulatory genes
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Goralski, T. J., J.-E. Edstrom, and B. S. Baker (1989). The sex determination locus transformer-2 of Drosophila encodes a polypeptide with similarity to RNA binding proteins. Cell, 56: 1011-1018.
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Li, H., and Baker, B. S., (1998). her, a sex differentiation gene of Drosophila, encodes a zinc finger protein with characteristics of ZFY-like proteins and is expressed independently of the sex determination hierarchy. Development, 125: 225-235.
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Garrett-Engele* C. M., Siegal*, M. L., Manoli, D. S., Williams, B. C., Li. H., and Baker, B. S., (2002). intersex, a gene required for female sexual development in Drosophila, is expressed in both sexes and functions together with doublesex to regulate terminal differentiation. Development, 129: 4661-4675. (* co-first authors)
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