The control of sexual development by the dsx branch of the sex hierarchy.

Having gained substantial knowledge of the hierarchy of regulatory genes that control sex we have focus much of our recent efforts on understanding how the dsx branch of the sex determination hierarchy controls growth, morphogenesis, and differentiation to generate the sexually dimorphisms that distinguish males and females. To most profitably approach how the processes of growth, morphogenesis, and differentiation are regulated by dsx in sexually dimorphic tissues requires an appreciation of the kinds of processes controlled by this branch of the hierarchy.

Examination of sex-specific aspects of development in flies (Figure 1) shows that it involves not only the patterning of the control of growth at an organismal level (females are bigger than males) and profoundly affects patterning and growth at the level of imaginal discs (the patterns of growth and morphogenesis of the genital disc in males and females are very different). Thus the sex determination hierarchy must control not only the expression of terminal differentiation genes in sexually dimorphic tissues, but also the patterns of growth and morphogenesis that build those tissues. Hence the dsx branch of the sex determination hierarchy controls a complex array of developmental processes that are not dissimilar to those controlled by other major developmental regulatory genes, for example the HOX genes. Thus understanding how the dsx branch to the sex hierarchy functions will entail addressing questions that are also central to other patterning hierarchies: How can the coordinated growth of a field of cells be brought about and limited? How can the cell fate choices across fields of cells be specified and coordinated?

Our strategy for gaining an understanding of how dsx controls growth, morphogenesis and differentiation, and how its activities are integrated with those of other developmental regulatory hierarchies is to focus on one part of the fly that shows extensive sexual dimorphism, and dissect how it's development and differentiation is controlled, not only by the sex determination hierarchy but also by other developmental hierarchies. We have therefore been dissecting genital imaginal disc development.

We chose the genital disc for these studies both because its adult derivatives show extensive sexual dimorphism, and because it displays some fascinating biology that we hoped to gain insight into.

The genital disc gives rise to the genitalia and analia. In contrast to most imaginal discs, which are essentially two-dimensional, the genital disc epithelium is a three-dimensional structure with distinct dorsal and ventral epithelia, which give rise to different adult structures. The female genital, the male genital and the anal primordia that make up the genital disc originate from within three embryonic tail segments, A8, A9, and A10. The progenitor cells of these three primordia fuse during late embryogenesis to form the genital disc precursor cells. Each of the three primordia that comprise the genital disc have specific fates in the two sexes (Figure 3). Thus the male primordium gives rise to the male genitalia in males and to the parovaria and part of the uterine wall in females. The female primordia gives rise to the female genitalia in females and an 8th tergite in males. The genital primordia gives rise to the distinctive male or female anal apparatus.

To identify genes that are deployed differently in the genital disc of males and females we have examined patterns of gene expression either directly by visualizing gene products (or reporter gene expression) in tissues, or via DNA microarray analysis. Together these studies have revealed several dozen new genes that function downstream of dsx in the development and/or differentiation of the genital disc. Some of these genes have been characterized to elucidate their roles in the sex-specific growth, morphogenesis and differentiation of the genital disc, and other genes await such characterization.

During the past few years these studies, and similar studies in other labs have provided a wealth of information about, and some surprising revelations into how sexual development is brought about. In addition, we are beginning to get our first insights into how instructions from the sex hierarchy and the hierarchies that build the basic body plan are integrated to insure proper development. Thus dsx has been shown to both control some genes involved in terminal sexual differentiation directly, and in other cases to act by modulating the activities of well-known signaling molecules [FGF, Wnt, and TGFß proteins] and transcription factors [bric-a-brac, and dachshund] to bring about sex-specific patterns of cell division, cell migration, morphogenesis and differentation. These findings show that dsx acts as a key switch that imposes sexual identity on developmental events in many tissues through its complex interactions with other regulatory hierarchies. Intriguingly, in many instances dsx appears to function together with the homeotic (HOX) genes to modulate these signaling molecules and transcription factors, and thus dsx may be profitably thought of as a sex-specific modulator of HOX gene function (Keisman et al., 2001; review: Christiansen, 2002).

Our current research in on sexual development includes the following topics:

  1. Although we know that DSX acts through FGF, Wnt, and TGFß, bric-a-brac, and dachshund we do not know the direct targets of DSX in modulating these factors. We are doing experiments to elucidate the molecular mechanism through which this regulation is achieved.
  2. We are characterizing many new targets of dsx identified through enhancer traps screens and DNA microarray experiments to elucidate whether they are direct or indirect targets of dsx and their roles in sexual development and the life of a fly.
  3. The hierarchies of genetic events during embryogenesis that establish the three primordia of the genital disc are being elucidated.

Papers on sexual development and differentiation

Original research publications

Belote, J. M., and B. S. Baker (1982). Sex determination in Drosophila melanogaster: analysis of trasnsformer-2 , a sex-transforming locus. Proc. Natl. Acad. Sci. (USA). 79: 1568-1572.

Belote, J. M., and B. S. Baker (1983). The dual functions of a sex determination gene in Drosophila melanogaster. Devel. Biol. 95: 512-517.

Belote, J. M., A. M. Handler, M. F. Wolfner, K. J. Livak, and B. S. Baker (1985). Sex-specific regulation of yolk protein gene expression in Drosophila. Cell 40: 339-348.

DiBenedetto, A. J., Lakich, D. M., Kruger, W. D., Belote, J.M., Baker, B. S., and M.F. Wolfner (1987) Sequences expressed sex-specifically in D. melanogaster adults. Devel. Biol,. 119:242-251.

K. C. Burtis, K. T. Coshigano, B. S. Baker and P. C. Wensink (1991). Drosophila doublesex proteins bind to a sex-specific yolk protein gene enhancer. EMBO J, 10: 2577-2582.

Chen, E. H., and Baker, B. S., (1997). Compartmental organization of the Drosophila genital imaginal disks. Development, 124: 205-218.

Keisman, E. L., and Baker, B. S., (2001). The Drosophila sex determination hierarchy modulates wingless and decapentaplegic signaling to sex-specifically deploy dachsund in the genital imaginal disc. Development 128: 1643-1656.

Keisman, E. L., Christiansen, A. E., and Baker, B. S., (2001) The sex determination gene doublesex (dsx) regulates the A/P organizer to direct sex-specific patterns of growth in the Drosophila genital imaginal disc. Developmental Cell, 1: 215-225.

Ahmad, S. M. and Baker, B. S., (2002). Sex-Specific deployment of FGF signaling in Drosophila recruits mesodermal cells into the male genital imaginal disc. Cell, 109, 651-661.

Arbeitman, M.*, Furlong, E.*, Imam, F.*, Johnson, E.*, Null, B.*, Baker, B. S., Davis, R., Krasnow, M., Scott, M., White, K.P..(2002). A genomic analysis of gene expression during the Drosophila life cycle. Science, 297: 2270-75. (*Co-first authors).


Belote, J. M., M. B. McKeown, D. J. Andrew, T. N. Scott, M. F. Wolfner, and B. S. Baker (1985). Control of sexual diferentiation in Drosophila melanogaster. CSHSQB 50: 605-614.

Christiansen, A. E., Keisman, E. L., Ahmad, S. M., and Baker, B. S., (2002). Sex comes in from the cold: the integration of sex and pattern. Trends in Genetics, 18: 510-516.