Alternative trans-splicing of constant and variable exons of a Drosophila axon guidance gene, lola.

longitudinals lacking (lola) is a complex Drosophila gene encoding at least 20 protein isoforms,each bearing the same N-terminal constant region linked to a different C-terminal variable region. Different isoforms specify different aspects of axon growth and guidance. We show here that lola mRNAs are generated by alternative trans-splicing of exons sequentially encoded by the same DNA strand. Chromosomal pairing facilitates interallelic trans-splicing,allowing complementation between mutations in the constant and those in the variable exons. We demonstrate that at least one variable exon is transcribed from its own promoter,and trans-spliced to the constant exons transcribed separately.

[1]  Csaba Finta,et al.  Intergenic mRNA Molecules Resulting fromtrans-Splicing* , 2002, The Journal of Biological Chemistry.

[2]  A. Bradley,et al.  Molecular mechanisms governing Pcdh-gamma gene expression: evidence for a multiple promoter and cis-alternative splicing model. , 2002, Genes & development.

[3]  Y. Jan,et al.  lola encodes a putative transcription factor required for axon growth and guidance in Drosophila. , 1994, Development.

[4]  K. Ui-Tei,et al.  Formation of the male-specific muscle in female Drosophila by ectopic fruitless expression , 2000, Nature Cell Biology.

[5]  A. Furger,et al.  Integrating mRNA Processing with Transcription , 2002, Cell.

[6]  B. Graveley.  Alternative splicing: increasing diversity in the proteomic world. , 2001, Trends in genetics : TIG.

[7]  R. Fisher,et al.  Novel Alternative Splicing and Nuclear Localization of HumanRGS12 Gene Products* , 2000, The Journal of Biological Chemistry.

[8]  A. Saxon,et al.  Multiple types of chimeric germ-line Ig heavy chain transcripts in human B cells: evidence for trans-splicing of human Ig RNA. , 1996, Journal of immunology.

[9]  Tom Maniatis,et al.  Promoter choice determines splice site selection in protocadherin alpha and gamma pre-mRNA splicing. , 2002, Molecular cell.

[10]  G. Orphanides,et al.  A Unified Theory of Gene Expression , 2002, Cell.

[11]  Bosiljka Tasic,et al.  Alternative pre-mRNA splicing and proteome expansion in metazoans , 2002, Nature.

[12]  Takayuki Horiuchi,et al.  Drosophila lola encodes a family of BTB-transcription regulators with highly variable C-terminal domains containing zinc finger motifs. , 2003, Gene.

[13]  E. Giniger,et al.  LOLA has the properties of a master regulator of axon-target interaction for SNb motor axons of Drosophila. , 1999, Developmental biology.

[14]  Fabien Mongelard,et al.  Molecular biology: Protein encoding by both DNA strands , 2001, Nature.

[15]  The Theory and Application of a New Method of Detecting Chromosomal Rearrangements in Drosophila melanogaster , 1954, The American Naturalist.

[16]  G. Reuter,et al.  Transgene analysis proves mRNA trans-splicing at the complex mod(mdg4) locus in Drosophila , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Toshiro Aigaki,et al.  Alternative splicing of lola generates 19 transcription factors controlling axon guidance in Drosophila , 2003, Nature Neuroscience.

[18]  N. Samani,et al.  Exon repetition in mRNA. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  F. Hegardt,et al.  Natural trans-splicing in carnitine octanoyltransferase pre-mRNAs in rat liver. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  E. B. Lewis,et al.  The Theory and Application of a New Method of Detecting Chromosomal Rearrangements in Drosophila melanogaster , 1954 .

[21]  Heike Brand,et al.  Natural trans-spliced mRNAs are generated from the human estrogen receptor-alpha (hER alpha) gene. , 2002, The Journal of biological chemistry.

[22]  D L Black,et al.  Splicing in the Inner Ear: a Familiar Tune, but What Are the Instruments? , 1998, Neuron.

[23]  Tom Maniatis,et al.  Promoter Choice Determines Splice Site Selection in Protocadherin α and γ Pre-mRNA Splicing , 2002 .

[24]  S. Yanagisawa,et al.  Heterogeneous Sp1 mRNAs in Human HepG2 Cells Include a Product of Homotypic trans-Splicing* , 2000, The Journal of Biological Chemistry.

[25]  J. C. Clemens,et al.  Drosophila Dscam Is an Axon Guidance Receptor Exhibiting Extraordinary Molecular Diversity , 2000, Cell.

[26]  I. Arkhipova,et al.  Promoter elements in Drosophila melanogaster revealed by sequence analysis. , 1995, Genetics.

[27]  T. Maniatis,et al.  An extensive network of coupling among gene expression machines , 2002, Nature.

[28]  J. T. Kadonaga,et al.  The Downstream Promoter Element DPE Appears To Be as Widely Used as the TATA Box in Drosophila Core Promoters , 2000, Molecular and Cellular Biology.

[29]  T. Südhof,et al.  α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis , 2003, Nature.

[30]  E. Giniger,et al.  Lola regulates midline crossing of CNS axons in Drosophila. , 2002, Development.

[31]  J. Fristrom,et al.  Relationships between protein isoforms and genetic functions demonstrate functional redundancy at the Broad-Complex during Drosophila metamorphosis. , 1997, Developmental biology.

[32]  T. Honjo,et al.  Synthesis and regulation of trans‐mRNA encoding the immunoglobulin ∊ heavy chain , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  C. W. Metz.  Chromosome studies on the Diptera. II. The paired association of chromosomes in the Diptera, and its significance , 1916 .

[34]  V. Corces,et al.  Trans-splicing as a novel mechanism to explain interallelic complementation in Drosophila. , 2002, Genetics.

[35]  R. Treisman,et al.  The POZ domain: a conserved protein-protein interaction motif. , 1994, Genes & development.

[36]  Heike Brand,et al.  Natural Trans-spliced mRNAs Are Generated from the Human Estrogen Receptor-α (hERα) Gene* , 2002, The Journal of Biological Chemistry.

[37]  W. Gelbart.  Synapsis-dependent allelic complementation at the decapentaplegic gene complex in Drosophila melanogaster. , 1982, Proceedings of the National Academy of Sciences of the United States of America.