Horabin Laboratory Jamila I. Horabin, Ph.D. Duke University Florida State University College of Medicine 1115 West Call Street Tallahassee, FL 32306-4300 Office: (850) 645-2820, COM 3300-G Dr. Horabin's Faculty Profile
Research Interests
Sex Determination in Drosophila Our major focus of interest is the mechanism of sex determination in the fruit fly, Drosophila melanogaster. How do flies know what sex to develop? How is this developmental decision made, executed and maintained so that cells in the body can perform the right functions? While the simple fruit fly may seem a far cry from humans, the surprising degree of conservation both at the level of protein sequences and of developmental regulators between flies and humans tells us that the information we gather from analyzing fruit flies will be directly applicable to understanding human development. The ratio of X chromosomes to the set of autosomes (the X:A ratio) is the primary sex determination signal in D. melanogaster. An X:A ratio of 1, as in XX individuals, is read as a female signal while a ratio of 1/2, as in XY individuals, is read as a male signal. The outcome of reading this ratio is imparted to the binary switch gene, Sex-lethal (Sxl) which serves as the masterswitch of sex determination. Sxl has 2 modes of operation; it is turned on in females while it remains off in males. Sxl controls sexual development as a splicing and translational regulator. It regulates dosage compensation (the process which corrects the level of gene expression from the sex chromosomes), turning off the system by both splicing regulation and translational repression. In regulating somatic sexual differentiation, Sxl promotes female differentiation by controlling the female specific splicing of transformer (tra). When tra is on female differentiation is driven through the female form of doublesex (dsx). The male form of dsx is the default mode, resulting in male differentiation.
Current Projects
Hedgehog Signaling and Sxl protein Recently, we have discovered a cross talk between Sxl and the Hedgehog (Hh) signaling pathway. Hh is a morphogen that specifies cell fate during development, patterning several different tissues. We find that production as well as the rate of nuclear entry of full-length Cubitus interruptus (Ci), the Hh signaling target, is enhanced by Sxl. This effect requires the cholesterol but not palmitoyl modification on Hh, and expands the zone of full-length Ci expression. Expansion of Ci activation and several of its downstream targets occurs. The enhancement of decapentaplegic, the Drosophila TGF-β homolog, in particular suggests a mechanism to generate different body sizes in the sexes; in Drosophila females are larger and this difference is controlled by Sxl. Consistent with this proposal, flies severely compromised for Hh show a greater size reduction in females than males. These results have implications for all organisms that are sexually dimorphic and use Hh for patterning. Future work is aimed at understanding the underlying molecular mechanism by which Sxl enhances the Hh signal. Given that several of the components of the Hh pathway have been implicated in tumors, a better understanding of Hh signaling will be important in curing various cancers.     Sex determination in the germ line and the function of Sxl. The other aspect of sex determination we are analyzing is how sexual identity in the germ line is established. Unlike the soma where expression of Sxl determines female identity, Sxl does not control all aspects of germ cell sexual identity. The sexual identity of the soma influences the germ line; a new pathway of genes that transmit a signal from the soma to the germ line is suggested by the data. Using genetics we have identified possible players in this signaling event and are cloning these genes. Their characterization will give us an understanding of how germ cells have their sexual identity programmed. Eventually, we plan to test whether other organisms use these same molecules for this process.
Selected References
Bopp, D., Horabin, J. I., Lersch, R. A., Cline, T. W. and Schedl, P. Expression of the Sex-lethal gene is controlled at multiple levels during Drosophila Oogenesis (1993). Development 118: 797-812. Horabin, J. I. and Schedl, P. Sex-lethal autoregulation requires multiple cis-acting elements upstream and downstream of the male exon and appears to pivot primarily on the male exon 5' splice site. (1993). Mol. Cell Biol. 13: 7734-7746. Horabin, J. I., Bopp, D., Waterbury, J. and Schedl, P. Selection and Maintenance of Sexual Identity in the Drosophila germline (1995). Genetics 141: 1521-1535. Waterbury, J., Horabin, J., Bopp, D. and Schedl, P. Sex determination in the Drosophila germline is dictated by the sexual identity of the surrounding soma. (2000). Genetics 155: 1741-1756. *Vied, C. and Horabin, J. I. The Sex Determination Master Switch, Sex-lethal, Responds to Hedgehog Signaling in the Drosophila Germline. (2001). Development 128: 2649-2660. Vied. C., Halachmi, N., Salzberg, A. and Horabin, J. I. Antizyme is a Target of Sex-lethal in the Drosophila Germline and appears to act downstream of Hedgehog to regulate Sex-lethal and Cyclin B. (2003). Dev. Biol. 253: 214-229. Horabin, J. I., Walthall, S., Vied, C and Moses, M. A Positive role for Patched in Hedgehog signaling revealed by the intracellular trafficking of Sex-lethal, the Drosophila Sex Determination Master Switch (2003). Development. 130: 6101-6109. *Article covered in ‘News and Views’ of Nature Cell Biology see: Greaves, S. The lethality of sex (2001). Nature Cell Biology 3: E208