Thomas Cline
Thomas ClineProfessor of Genetics and DevelopmentE-mail: sxlcline@berkeley.edu |
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Full Directory InformationResearch Interests
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We are studying how sexual dimorphism in the fruit fly, Drosophila melanogaster, is genetically programmed, how that programming is executed, and how it evolved. These studies address a wide variety of questions at the molecular level that have relevance far beyond the sex determination field. Our work draws on the enormous amount known about the unusual master regulatory switch gene Sex-lethal (Sxl), which exerts its control through interactions with RNA.
Current Projects
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Sxl occupies a unique and central position among the genes that control Drosophila sex. It is the direct target of the sex-determination signal, X-chromosome dose. The double dose of "X signal elements" (XSEs) in chromosomal females (XX) turns Sxl "ON" by activating Sxl transcription at the "establishment" promoter of Sxl in the soma, while the single dose of XSEs in males (XY) leaves Sxl "OFF." Differences between the sexes arise as a consequence of this sex-specific control. Sxl assesses somatic XSE dose only briefly soon after fertilization. The pulse of Sxl protein thereby generated only in females engages a positive feedback loop involving alternative splicing of pre-mRNA derived from the "maintenance" promoter of Sxl, which is active in both sexes and in all tissues; hence, Sxl is active in females throughout development, while full-length Sxl proteins are never made in males. These proteins direct female differentiation and X-chromosome dosage compensation by interacting with the RNA products of more functionally specialized switch genes. Controls on Sxl mRNA translation and turnover, and on Sxl protein turnover also seem to be important for the operation of this system. Among known sex-switch genes, only Sxl acts in both somatic and germline cells. In germ cells Sxl is required for both oogenesis and meiotic recombination. Little is known about the regulation and functioning of Sxl in germ cells except that it differs remarkably from that in the soma. In the gonad cell-cell communication plays a key role in Sxl control.
We are engaged in structure-function studies of Sxl to understand the molecular origins and functions of the gene's diverse protein products. Because SXL belongs to the largest family of RNA binding proteins, these studies can help us understand how such proteins operate. The unique features of sex-specific genetics allow us to employ powerful positive genetic selection schemes and thereby exploit mutagenesis approaches that would otherwise be impractical. We combine genetic andbiochemical approaches so that we can relate in vitro results to the far more complex world in vivo with confidence. In the course of exploring Sxl's somatic sex-determination functions, we discovered a branch in the known regulatory gene hierarchy between Sxl and tra that controls egg-laying and sperm-storage behavior. Efforts are underway to define the tissues and SXL gene targets involved in this branch.
We are elucidating surprising differences between Sxl regulation and functioning in the gonad compared to that in the rest of the animal. As in other aspects of our work, we rely on a variety of powerful suppressor screens to help us identify genes upstream and downstream of Sxl in the germline, and genes that control sexual behavior. These efforts are providing insight into general differences between somatic and germline cells with respect to gene regulation and evolutionary pressures. They will also help us understand the molecular basis for a remarkable host/parasite relationship we discovered: infection of germline-defective Sxl mutant females with Wolbachia bacteria suppresses their oogenesis defects in an allele-specific fashion.
Because sex-determination signals are among the most rapidly evolving aspects of developmental programming, they provide unique opportunities for understanding how developmental programs evolve. All Drosophila XSEs, and perhaps even Sxl itself, have important non-sex-specific (likely ancestral) functions later in development. We are studying how these genes were recruited to the sex-determination pathway. These efforts include genetic selections yielding mutations in the sex-determination system of D.virilis, a species 45 Myr distant from melanogaster. They also include biochemical efforts to understand how the XSE genes come to be expressed during a period when nearly all other genes are silent.
Selected Publications
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Recruitment of the proneural gene scute to the Drosophila sex-determination pathway. [L.A. Wrischnik, J.R. Timmer, L.A. Megna, and T.W. Cline (2003) Genetics 165, 2007-2027]
A host-parasite interaction suppresses oogenesis defects of Drosophila sex-determination gene mutants. [D. J. Starr and T.W. Cline (2002) Nature 418, 76-79]
An extracellular activator of the Drosophila JAK/STAT pathway is a sex-determination signal element. [L. Sefton, J. R. Timmer, Y. Zhang, F. Beranger, and T. W. Cline (2000) Nature 405, 970-973]
Functioning of the Drosophila integral U1/U2 protein Snf independent of U1 and U2 small nuclear ribonucleoprotein particles is revealed by snf+ gene dose effects. [T.W. Cline, D.Z. Rudner, D.A. Barbash, M. Bell and R. Vutien (1999) Proc. Natl. Acad. Sci. USA 96, 14451-14458]
Key aspects of the primary sex determination mechanism are conserved across the genus Drosophila. [J. W. Erickson and T. W. Cline (1998) Development 125, 3259-3268]
Vive la différence: males vs. females in flies vs. worms. [T.W. Cline and B.J. Meyer (1996) Annual Review of Genetics 30, 637-701]
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