Splicing Regulation in Drosophila Sex Determination

Förch, Patrik; Valcárcel, Juan

doi:10.1007/978-3-662-09728-1_5

Cited by 46 publications

(44 citation statements)

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“…Somatic sex determination in Drosophila is regulated by a cascade of alternative splicing, under the control of the SR-like TRA and TRA2 proteins, among others (Forch and Valcarcel 2003;Rabinow and Samson 2010). Mammalian SRm160 interacts directly with the mammalian TRA2 ortholog (Eldridge et al 1999), suggesting that the Drosophila protein might participate in somatic sex determination.…”

Section: Srm160 Functions In Somatic Sex Determinationmentioning

confidence: 99%

“…Among them is the mammalian ortholog of the Drosophila protein Transformer 2 (Blencowe et al 1998;Eldridge et al 1999), another SR-related protein which influences alternative-splice site selection. In Drosophila, TRA2 directly binds and influences splicing of the dsx transcript as part of a SR-protein complex essential to somatic sex determination (Forch and Valcarcel 2003;Rabinow and Samson 2010). SRm160 and SR proteins function together in the first step of spliceosome formation to facilitate the interaction of the U1 subunit of the spliceosome with its target pre-mRNA (Blencowe et al 1998).…”

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Multifunctional RNA Processing Protein SRm160 Induces Apoptosis and Regulates Eye and Genital Development in Drosophila

et al. 2014

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SRm160 is an SR-like protein implicated in multiple steps of RNA processing and nucleocytoplasmic export. Although its biochemical functions have been extensively described, its genetic interactions and potential participation in signaling pathways remain largely unknown, despite the fact that it is highly phosphorylated in both mammalian cells and Drosophila. To begin elucidating the functions of the protein in signaling and its potential role in developmental processes, we characterized mutant and overexpression SRm160 phenotypes in Drosophila and their interactions with the locus encoding the LAMMER protein kinase, Doa. SRm160 mutations are recessive lethal, while its overexpression generates phenotypes including roughened eyes and highly disorganized internal eye structure, which are due at least in part to aberrantly high levels of apoptosis. SRm160 is required for normal somatic sex determination, since its alleles strongly enhance a subtle sex transformation phenotype induced by Doa kinase alleles. Moreover, modification of SRm160 by DOA kinase appears to be necessary for its activity, since Doa alleles suppress phenotypes induced by SRm160 overexpression in the eye and enhance those in genital discs. Modification of SRm160 may occur through direct interaction because DOA kinase phosphorylates it in vitro. Remarkably, SRm160 protein was concentrated in the nuclei of precellular embryos but was very rapidly excluded from nuclei or degraded coincident with cellularization. Also of interest, transcripts are restricted almost exclusively to the developing nervous system in mature embryos.

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Section: Srm160 Functions In Somatic Sex Determinationmentioning

confidence: 99%

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confidence: 99%

Multifunctional RNA Processing Protein SRm160 Induces Apoptosis and Regulates Eye and Genital Development in Drosophila

et al. 2014

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“…The best characterized example of this is the sex-determination pathway in Drosophila (Forch and Valcarcel 2003). This pathway involves five genes-Sex-lethal (Sxl), transformer (tra), male-specific lethal-2 (msl-2), doublesex (dsx), and fruitless (fru)-that are each spliced differently in male and female flies.…”

Section: Introductionmentioning

confidence: 99%

A computational and experimental approach toward a priori identification of alternatively spliced exons

Philipps

Park²,

Graveley³

2004

RNA

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Alternative splicing is a powerful means of regulating gene expression and enhancing protein diversity. In fact, the majority of metazoan genes encode pre-mRNAs that are alternatively spliced to produce anywhere from two to tens of thousands of mRNA isoforms. Thus, an important part of determining the complete proteome of an organism is developing a catalog of all mRNA isoforms. Alternatively spliced exons are typically identified by aligning EST clusters to reference mRNAs or genomic DNA. However, this approach is not useful for genomes that lack robust EST coverage, and tools that enable accurate prediction of alternatively spliced exons would be extraordinarily useful. Here, we use comparative genomics to identify, and experimentally verify, potential alternative exons based solely on their high degree of conservation between Drosophila melanogaster and D. pseudoobscura. At least 40% of the exons that fit our prediction criteria are in fact alternatively spliced. Thus, comparative genomics can be used to accurately predict certain classes of alternative exons without relying on EST data.

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“…Alternative splicing plays key roles in developmental processes, such as Drosophila sex determination, and defects in alternative splicing are commonly associated with human disorders, such as spinal muscular atrophy (12,13). Thus, understanding the molecular details of alternative splicing mechanisms has global implications for understanding both normal and disease states.…”

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Control of Alternative Splicing by Signal-dependent Degradation of Splicing-regulatory Proteins

Katzenberger

Marengo

Wassarman

2009

Journal of Biological Chemistry

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Alternative pre-mRNA splicing is a major gene expression regulatory mechanism in metazoan organisms. Proteins that bind pre-mRNA elements and control assembly of splicing complexes regulate utilization of pre-mRNA alternative splice sites. To understand how signaling pathways impact this mechanism, an RNA interference screen in Drosophila S2 cells was used to identify proteins that regulate TAF1 (TBP-associated factor 1) alternative splicing in response to activation of the ATR (ATM-RAD3-related) signaling pathway by the chemotherapeutic drug camptothecin (CPT). The screen identified 15 proteins that, when knocked down, caused the same change in TAF1 alternative splicing as CPT treatment. However, combined RNA interference and CPT treatment experiments indicated that only a subset of the identified proteins are targets of the CPT-induced signal, suggesting that multiple independent pathways regulate TAF1 alternative splicing. To understand how signals modulate the function of splicing factors, we characterized one of the CPT targets, Tra2 (Transformer-2). CPT was found to downregulate Tra2 protein levels. CPT-induced Tra2 down-regulation was ATR-dependent and temporally paralleled the change in TAF1 alternative splicing, supporting the conclusion that Tra2 directly regulates TAF1 alternative splicing. Additionally, CPT-induced Tra2 down-regulation occurred independently of new protein synthesis, suggesting a post-translational mechanism. The proteasome inhibitor MG132 reduced CPT-induced Tra2 degradation and TAF1 alternative splicing, and mutation of evolutionarily conserved Tra2 lysine 81, a potential ubiquitin conjugation site, to arginine inhibited CPT-induced Tra2 degradation, supporting a proteasome-dependent alternative splicing mechanism. We conclude that CPT-induced TAF1 alternative splicing occurs through ATR-signaled degradation of a subset of splicing-regulatory proteins.Alternative splicing is a fundamental mechanism operating in metazoan organisms to regulate protein expression (1-3). In humans and Drosophila, 30 -95% of pre-mRNAs undergo alternative splicing, resulting in mature mRNAs that encode proteins with different sequences or that contain a premature stop codon and are subject to degradation (4 -11). Alternative splicing plays key roles in developmental processes, such as Drosophila sex determination, and defects in alternative splicing are commonly associated with human disorders, such as spinal muscular atrophy (12, 13). Thus, understanding the molecular details of alternative splicing mechanisms has global implications for understanding both normal and disease states.At its basic level, the choice of splicing pattern for a pre-mRNA involves the regulation of spliceosome assembly on introns to be excised. Spliceosomes contain five small nuclear ribonucleoproteins (snRNPs) 3 (U1, U2, U4, U5, and U6) and numerous regulatory proteins, including the heterodimeric complex U2AF (U2 auxiliary factor) (14 -16). Spliceosomes serve to define 5Ј and 3Ј splice sites at exon/intron boundaries and carry...

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Splicing Regulation in Drosophila Sex Determination

Cited by 46 publications

References 135 publications

Multifunctional RNA Processing Protein SRm160 Induces Apoptosis and Regulates Eye and Genital Development in Drosophila

Multifunctional RNA Processing Protein SRm160 Induces Apoptosis and Regulates Eye and Genital Development in Drosophila

A computational and experimental approach toward a priori identification of alternatively spliced exons

Control of Alternative Splicing by Signal-dependent Degradation of Splicing-regulatory Proteins

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