Regulation of sex-specific RNA splicing at the Drosophila doublesex gene: cis-acting mutations in exon sequences alter sex-specific RNA splicing patterns.

Nagoshi, Rod; Baker, Bruce S.

doi:10.1101/gad.4.1.89

Cited by 158 publications

(123 citation statements)

References 55 publications

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“…Transgenic chromosomal males subjected to periodic heat shocks through development had no overt signs of intersexuality, suggesting that these individuals are not competent to (8,36). Due to the absence of the enhancer, the mRNA produced by the dsxfs allele is processed exclusively in the male-specific pattern regardless of chromosomal sex.…”

Section: Resultsmentioning

confidence: 99%

A human homologue of the Drosophila sex determination factor transformer-2 has conserved splicing regulatory functions.

Dauwalder

Amaya-Manzanares

Mattox

1996

Proc. Natl. Acad. Sci. U.S.A.

113

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Regulation of gene expression through alternative pre-mRNA splicing appears to occur in all metazoans, but most of our knowledge about splicing regulators derives from studies on genetically identified factors from Drosophila.Among the best studied of these is the transformer-2 (TRA-2) protein which, in combination with the transformer (TRA) protein, directs sex-specific splicing of pre-mRNA from the sex determination gene doublesex (dsx). Here we report the identification of htra-2a, a human homologue of tra-2. Two alternative types of htra-2a cDNA clones were identified that encode different protein isoforms with striking organizational similarity to Drosophila tra-2 proteins. When expressed in flies, one hTRA-2a isoform partially replaces the function of Drosophila TRA-2, affecting both female sexual differentiation and alternative splicing of dsx pre-mRNA. Like Drosophila TRA-2, the ability of hTRA-2a to regulate d&x is femalespecific and depends on the presence of the dsx splicing enhancer. These results demonstrate that htra-2a has conserved a striking degree of functional specificity during evolution and leads us to suggest that, although they are likely to serve different roles in development, the tra-2 products of flies and humans have similar molecular functions.Despite the fact that a large fraction of identified cellular pre-mRNAs undergo alternative splicing, few vertebrate factors have been identified that affect splicing patterns. Of those factors so far studied, the evidence for a role in the regulation of splicing is best for the SR proteins, a family of RNA binding proteins that contain extensive regions rich in arginine and serine (RS domains) (for review, see ref. 1). Several lines of evidence suggest these domains may facilitate interactions with other RNA binding proteins. While SR proteins are known to play vital roles during constitutive pre-mRNA splicing both in the initiation of spliceosome assembly and in interactions between small nuclear ribonucleoproteins they have also been shown to affect the selection of alternative 5' splice sites in a variety of artificial and natural substrates in a concentration dependent manner. In addition, several SR proteins are known to interact with the purine-rich splicing enhancer elements found in some vertebrate exons. While these observations strongly suggest a role for SR proteins in regulating splicing, there is still little direct evidence that vertebrate SR proteins normally direct the developmentally specific alternative splicing of any particular cellular pre-mRNAs in vivo.Proteins with established roles in developmental regulation of splicing have been identified in Drosophila through genetic analysis (2-7). Many of these proteins form a cascade of splicing factors that directs sexual differentiation in the fly. Two SR-related proteins, encoded by the transformer (tra) and transformer-2 (tra-2) genes, play a central role in this pathway (8). However, unlike the vertebrate SR proteins described above, these SR-related splicing factors...

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Section: Resultsmentioning

confidence: 99%

A human homologue of the Drosophila sex determination factor transformer-2 has conserved splicing regulatory functions.

Dauwalder

Amaya-Manzanares

Mattox

1996

Proc. Natl. Acad. Sci. U.S.A.

113

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“…The dsxKE consists of six 13-nucleotide repeat sequences (R1-R6; Baker 1989) and a purine-rich element (PRE), which together activate a weak female-specific 3' splice site located 300 nucleotides upstream (Lynch and Mani atis 1995). The activity of the dsxRE requires the regu latory proteins Transformer (Tra) and Transformer 2 (Tra2) (Nagoshi and Baker 1990;Hedley and Maniatis 1991;Hoshijima et al 1991;Ryner and Baker 1991) and one or more members of the SR family of general splicing factors (Tian and Maniatis 1993).…”

mentioning

confidence: 99%

The splicing factor U2AF35 mediates critical protein-protein interactions in constitutive and enhancer-dependent splicing.

Zuo¹,

Maniatis²

1996

Genes Dev.

279

287

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The splicing factor U2AF (U2 snRNP auxiliary factor] is a heterodimer with subunits of 65 and 35 kD (U2AF^^ and U2AF^^). U2AF^^ binds specifically to 3' splice sites, but previous studies failed to demonstrate a function for U2AF^^. Here, we report that U2AF^^ is required for constitutive splicing and also functions as a mediator of enhancer-dependent splicing. Nuclear extracts deficient in U2AF^^ were inactive; however, both constitutive and enhancer-dependent splicing could be restored by the addition of purified recombinant U2AF^^. In vitro protein-RNA interaction studies with pre-mRNAs containing either a constitutive or regulated splicing enhancer revealed that U2AF^^ directly mediates interactions between U2AF^^ and proteins bound to the enhancers. Thus, U2AF^^ functions as a bridge between U2AF^^ and the enhancer complex to recruit U2AF^^ to the adjacent intron.[Key Words: U2AF; RNA; splicing; pre-mRNAs; SR proteins) Received March 1, 1996; revised version accepted April 22, 1996.The production of metazoan messenger RNAs (mRNAs) requires the accurate removal of introns from pre-messenger RNAs (pre-mRNAs) by RNA splicing (for review, see Moore et al. 1993). Initial recognition of the correct pairs of 5' and 3' splice sites by the splicing apparatus is a critical step in the processing of both constitutively and alternatively spliced pre-mRNAs (for review,

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“…We therefore determined the effects of the two DSX proteins on cycling of sxe1 mRNA at ZT 3 and ZT 19, the times of trough and peak, respectively, in XX and XY flies with various dsx alleles. (Nagoshi and Baker 1990). As In the head and thorax, sxe1 is mainly expressed in cells associated with long mechanosensory bristles of males (macrochaetae, A and B), but absent in females (not shown).…”

Section: Resultsmentioning

confidence: 97%

A Male-Specific Fatty Acid ω-Hydroxylase, SXE1, Is Necessary for Efficient Male Mating in Drosophila melanogaster

2008

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In Drosophila, sexual differentiation, physiology, and behavior are thought to be mediated by numerous male-and female-specific effector genes whose expression is controlled by sex-specifically expressed transcriptional regulators. One such downstream effector gene, sex-specific enzyme 1 (sxe1, cyp4d21), has been identified in a screen for genes with sex-biased expression in the head. Sxe1 was also identified in another screen as a circadian regulated gene. Here, we analyzed the spatial and temporal regulation of sxe1 and identified a function for this gene in male courtship. We show that male-specific transcriptional regulator DSX M and the clock genes are necessary for cycling of sxe1 mRNA during the diurnal cycle. Similar to sxe1 mRNA, expression of SXE1 protein oscillates in a diurnal fashion, with highest protein levels occurring around midnight. SXE1 protein expression is restricted to nonneuronal cells associated with diverse sensory bristles of both the chemo-and mechanosensory systems. Suppression or knockout of sxe1 significantly reduces mating success throughout the diurnal cycle. Finally, the metabolomic profile of wild-type and sxe1 mutant males revealed that sxe1 likely functions as a fatty acid v-hydroxylase, suggesting that male courtship and mating success is mediated by small compounds generated by this enzyme. DEVELOPMENT and differentiation of sex-specific structures and organs, and the establishment of sex-specific physiological/neuroanatomical traits, are essential processes common to virtually all animals. In Drosophila melanogaster, somatic differentiation of male and female flies is regulated by sex-specific splicing regulators including SEX-LETHAL (SXL) and TRANS-FORMER (TRA) that lead to the expression of maleand female-specific spliced isoforms of the transcription factors, FRUITLESS (FRU

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Regulation of sex-specific RNA splicing at the Drosophila doublesex gene: cis-acting mutations in exon sequences alter sex-specific RNA splicing patterns.

Cited by 158 publications

References 55 publications

A human homologue of the Drosophila sex determination factor transformer-2 has conserved splicing regulatory functions.

A human homologue of the Drosophila sex determination factor transformer-2 has conserved splicing regulatory functions.

The splicing factor U2AF35 mediates critical protein-protein interactions in constitutive and enhancer-dependent splicing.

A Male-Specific Fatty Acid ω-Hydroxylase, SXE1, Is Necessary for Efficient Male Mating in Drosophila melanogaster

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