Disease relevance of tra2

• In this paper we show that tra-2 produced in Escherichia coli binds specifically to a site within the female-specific exon of dsx pre-mRNA [1].
• Feminization of the germline depends upon the constitutively expressed transformer-2 (tra-2) gene, but does not seem to require a functional dsx gene [2].

High impact information on tra2

• We find that Tra2 interacts with itself, with the splicing regulator Transformer, and with the general splicing factor SF2 in vitro and in the yeast two-hybrid system [3].
• These results demonstrate that both protein-RNA and protein-protein interactions are involved in tra2-dependent activation and repression of alternative splicing [3].
• Characterization of the proteins associated with affinity-purified complex formed on dsx pre-mRNA reveals the presence of Tra, Tra2, SR proteins, and additional unidentified components [4].
• We conclude that Tra, Tra2, and SR proteins are essential components of a splicing enhancer complex [4].
• Sex-specific splicing and polyadenylation of dsx pre-mRNA requires a sequence that binds specifically to tra-2 protein in vitro [1].

Biological context of tra2

• The transformer-2 (tra-2) gene of Drosophila melanogaster plays essential roles in both sexual differentiation in the female soma and spermatogenesis in the male germ line [5].
• The translation of products from a tra-2-lacZ fusion gene in both sexes suggests that the female-specific functioning of tra-2 in somatic tissues is not attributable to a translational mechanism [5].
• Temperature-shift experiments with temperature-sensitive tra-2 mutants demonstrate that within single cell lineages tra-2+ function is required at several times, and probably continuously, during development for the occurrence of a series of determinative decisions necessary for female sexual differentiation [6].
• Four repeat elements identical to the D. melanogaster TRA/TRA-2 binding sites have been found in the untranslated region of the female-specific exon 4, predicting a common regulatory splicing mechanism in all studied species of Diptera [7].
• Moreover, by altering the dosage of either the transgenes or the endogenous tra2(+) loci, one can vary the effect over a wide range of mutant phenotypes [8].

Anatomical context of tra2

• We show that although two transcripts are expressed male specifically in the germ line, the tra-2 transcripts expressed in the soma are not sex-specific [5].
• att, a target for regulation by tra2 in the testes of Drosophila melanogaster, encodes alternative RNAs and alternative proteins [9].
• Chromosomal females homozygous for tra or tra-2 have no detectable hemolymph vitellogenins, while those homozygous for tra-2OTF exhibit appreciable levels of these proteins [10].
• Female flies mutant for alleles of Sex-lethal, defective in sex determination, or null alleles of transformer or transformer-2 are converted into phenotypic males that formed male-specific abdominal muscles [11].
• We find that Tra2 is expressed at higher levels in primary spermatocytes of males than in other cell types [12].

Associations of tra2 with chemical compounds

• Independently of pre-mRNA, SRm160/300 specifically interacts with U2 snRNP and with a human homolog of the Drosophila alternative splicing regulator Transformer 2, which binds to purine-rich ESEs [13].
• The products of the tra-2 gene are also required for continuous transcription of the yolk-protein genes, suggesting that the pathway inhibited by the cycloheximide is that of the sex-determination hierarchy [14].
• 20-hydroxyecdysone can affect the transcription of these genes in males and females, as can mutations in the sex-determining genes tra, tra-2, ix and dsx [14].
• Orcein-stained testis preparations from tra-2 males reveal a spermiogenic defect similar to that associated with dominant male sterile (X; autosome) translocations [15].
• All isoforms of BmTRA-2 protein contain two arginine/serine-rich domains and one RNA recognition motif, showing striking organizational similarity to Drosophila TRA-2 proteins [16].

Regulatory relationships of tra2

• These and other results support the model that the tra-2+ and tra+ loci act to control the expression of the bifunctional doublesex (dsx) locus [6].
• The mechanisms of this process were investigated using an in vitro system in which recombinant TRA/TRA2 could activate the female-specific 5'-splice site of fru [17].
• We suggest that tra-2 activity in somatic tissues is regulated through a post-translational sex-specific interaction with the product of the tra gene rather than through the expression of a female-specific tra-2 polypeptide [5].
• Sex-specific processing of the Drosophila exuperantia transcript is regulated in male germ cells by the tra-2 gene [18].

Other interactions of tra2

• We show that mutations in the Drosophila LAMMER kinase, Doa, alter sexual differentiation and interact synergistically with tra and tra2 mutations [19].
• Furthermore, using a two-hybrid system, we show protein-protein interactions between RBP1 and itself and between RBP1 and TRA-2 [20].
• We report here that tra-2 is required in male germ cells for efficient male-specific processing of exu RNA; in the absence of tra-2, X/Y males produce a new mRNA which is processed at its 3' end so that it contains sequences normally specific to the female 3' untranslated region [18].
• Therefore, the wild-type products of the genes Sex-lethal, transformer and transformer-2 act to prevent the differentiation of male-specific muscles in female flies [11].
• These arginine-rich regions contain stretches of arginine-serine dipeptides like those found in transformer, transformer-2, and suppressor-of-white-apricot proteins, all of which have been identified as regulators of mRNA splicing in Drosophila melanogaster [21].

Analytical, diagnostic and therapeutic context of tra2

• Sequence analysis of the tra-2 gene and 10 tra-2 cDNA clones coupled with nuclease protection analysis reveals a variety of alternatively spliced tra-2 mRNAs that each encode one of four distinct but overlapping polypeptides [5].
• Molecular cloning of a mouse homologue for the Drosophila splicing regulator Tra2 [22].

References