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.

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People

Patricia Graham - Post-doc

Gretchen Calhoun - Staff

Jill Penn - Graduate Student

Papers

(PDFs)

 

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.

Jinks, T. M., G. Calhoun, et al. (2003). "Functional conservation of the sex-lethal sex determining promoter, Sxl-Pe, in Drosophila virilis." Dev Genes Evol 213(4): 155-65.

Graham, P., Penn, J.K.M., Schedl, P. (2003) Masters change, slaves remain. BioEssays. 25: 1-4

Waterbury, J.A., Horabin, J.I. Bopp, D. and Schedl, P. (2000) Sex determination in the Drosophila germline is dictated by the sexual identity of the surrounding soma. Genetics. 155(4), 1741-56.

JJinks, T., Polydorides, A., Calhoun, G., and Schedl, P. (2000) The JAK/STAT Signaling pathway is required for the initial choice of sexual identity in D. melanogaster. Molecular Cell, 5, 581-587.

Yanowitz et al. (1999). An N-terminal truncation uncouples the sex-transforming and dosage compensation functions of Sxl. Mol. Cell Biol. Vol. 19, 4:3018-3028.

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.

Kramer, S., Jinks, T., Schedl, P., Gergen, J.P. (1999). Direct activation of Sex-lethal transcription by the Drosophila Runt protein. Development, 126:191-200.

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.

Hughson, F.M. and Schedl, P. (1999) Two domains and one RNA: a molecular threesome. Nature Structural Biology. Vol. 6, 6:49-502.

Samuels, M., Deshpande, G., and Schedl, P. (1998) Activities of the Sex-lethal protein in RNA binding and protein:protein interactions. Nucleic Acids Research. Vol. 26, 11:2625-2637.

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.

Deshpande, G., Samuels, M.E., and Schedl, P. (1996). Sex-lethal interacts with splicing factors in vitro and in vivo. MCB, 16:5036-5047.

Horabin, J., and P. Schedl (1996). Splicing of the Drosophila Sex-lethal early transcripts involves exon skipping that is independent of Sex-lethal protein. RNA, 2:1-10.

Horabin, J.I., D. Bopp, J. Waterbury, and P. Schedl (1995). Selection and maintenance of sexual identity in the Drosophila germline. Genetics, 141:1521-1535.

Deshpande, G., J. Stukey, and P. Schedl (1995). scute (sis-b) Function in Drosophila sex determination. MCB, 15:4430-4440.

Estes, P.A., L.N. Keyes, and P. Schedl (1995). Multiple response elements within the Sex-lethal early promoter ensure its female-specific expression pattern. MCB, 15:904-917.

Samuels, M., D. Bopp, R.A. Colvin, R. Roscigno, M.A. Garcia-Blanco, and P. Schedl (1994). RNA binding by Sxl proteins in vitro and in vivo. Mol. Cell. Biol. 14:4975-4990.

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.

Horabin, J. and P. Schedl (1993). Regulated splicing of the Drosophila Sex-lethal male exon involves a blockage mechanism. Mol. Cell Biol. 13:1408-1414.

Bopp, D., J.I. Horabin, R.A. Lersh, T.W. Cline, and P. Schedl (1993). Expression of the Sex-lethal gene is controlled at multiple levels during Drosophila oogenesis. Development 118:797-812.

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.

Bopp, D., L.R. Bell, T.W. Cline and P. Schedl (1991). Developmental expression of female-specific sex-lethal proteins in D. melanogaster. Genes & Devel. 5:403-415.

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.

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