Sex determination & Dosage Compensation
Research on sex determination focuses on the binary switch gene Sex-lethal (Sxl). Sxl plays a pivotal role in the development of sexual dimorphism in the fruit fly. The special importance of Sxl may be understood by considering three of the central themes in development: 1) Pathway initiation: What mechanisms enable a cell to choose between alternative developmental programs? 2) Determination: Once that choice has been made, what mechanisms ensure that that cells remain committed to the correct pathway? 3) Differentiation: What mechanisms ensure the proper elaboration of the developmental program? Sxl is unusual in that it functions in all three of these processes. Additionally Sxl is of interest because its' developmental functions are controlled by both transcriptional and post-transcriptional regulatory mechanisms. Pathway initiation depends upon a counting system that assess the X chromosome to autosome ratio and regulates the activity of the Sxl-establishment promoter, Sxl-Pe. The Sxl-Pe promoter is turned on female (2X/2A) cells while its kept off in male (1X/2A) cells. Protein products from the Sxl-Pe transcripts in females induce the permanent activation of the Sxl gene by directing the female-specific splicing of transcripts from the Sxl-maintenance promoter, Sxl-Pm. Once activated, the Sxl gene ensures that the female determined state is remembered during the rest development. The memory mechanism is an autoregulatory feed back loop in which Sxl proteins promote their own synthesis by directing the female splicing of Sxl-Pm pre-mRNAs. Finally Sxl orchestrates female differentiation by regulating several gene cascades at the level of splicing and translation.
Patricia Graham - Post-doc
Gretchen Calhoun - Staff
Jill Penn - Graduate Student
Greenberg, A.J, J.L. Yanowitz and P. Schedl, The Drosophila GAGA factor is required for dasage compensation in males and for the formation of the male-specific-lethal complex chromatin entry site at 12DE. Genetics, 200. 166(1): p.279-89.
Desphande, G., Calhoun, G., and Schedl, P. (1999). The N-terminal domain of Sxl protein disrupts Sxl autoregulation in females and promotes female-specific splicing of tra in males. Development 126: 2841-2853.
Deshpande, G., Calhoun, G., Yanowitz, J.L. and Schedl, P. (1999) Novel functions of nanos in down regulating mitosis and transcription during the development of Drosophila germline. Cell, 99, 271-281.
Waterbury, J., Jackson, L., and Schedl, P. (1999). Analysis of the doublesex female protein in drosophila melanogaster: role in sexual differentiation and behavior and dependence on intersex. Genetics 152: 1653-1667.
Bopp, D., Calhoun, G., Horabin, J.I., Samuels, M.E., and Schedl, P. (1996). Sex-specific control of Sex-lethal is a conserved mechanism for sex determination in the genus Drosophila. Development, 122:971-982.
Horabin, J., and P. Schedl (1993), Sex-lethal autoregulation requires multiple cis-acting elements upstream and downstream of the male exon, and appears to depend largely on controlling the use of the male exon 5' splice site. Mol. Cell Biol., 13:7734-7746.
Keyes, L., T. W. Cline and P. Schedl (1992). The primary sex-determination signal in Drosophila acts at level of transcription. Cell 68:933-943.
Bell, L.R., J.I. Horabin, P. Schedl and T.W. Cline (1991). Positive autoregulation of sex-lethal by alternative splicing maintains the female determined state in Drosophila. Cell, 65:229-239
Samuels, M.E., P. Schedl and T.W. Cline (1991). The complex set of late transcripts from the Drosophila sex determination gene Sex-lethal encodes multipe related polypeptides. Mol. Cell. Biol. 11:3584-3602.
Salz, H., E. Maine, L. Keyes, M. Samuels, T. Cline and P. Schedl (1989). The Drosophila female-specific sex determination gene, Sex-lethal, has stage, tissue and sex specific RNAs suggesting multiple modes of regulation. Genes and Development 3:708-719.