Homologues of the Caenorhabditis elegans Fox-1 protein are neuronal splicing regulators in mammals.
A vertebrate homologue of the Fox-1 protein from C. elegans was recently shown to bind to the element GCAUG and to act as an inhibitor of alternative splicing patterns in muscle. The element UGCAUG is a splicing enhancer element found downstream of numerous neuron-specific exons. We show here that mouse Fox-1 (mFox-1) and another homologue, Fox-2, are both specifically expressed in neurons in addition to muscle and heart. The mammalian Fox genes are very complex transcription units that generate transcripts from multiple promoters and with multiple internal exons whose inclusion is regulated. These genes produce a large family of proteins with variable N and C termini and internal deletions. We show that the overexpression of both Fox-1 and Fox-2 isoforms specifically activates splicing of neuronally regulated exons. This splicing activation requires UGCAUG enhancer elements. Conversely, RNA interference-mediated knockdown of Fox protein expression inhibits splicing of UGCAUG-dependent exons. These experiments show that this large family of proteins regulates splicing in the nervous system. They do this through a splicing enhancer function, in addition to their apparent negative effects on splicing in vertebrate muscle and in worms.
Underwood
Jason G
JG
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California 90095-1662, USA.
Boutz
Paul L
PL
Dougherty
Joseph D
JD
Stoilov
Peter
P
Black
Douglas L
DL
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D005091:Exons; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns; D051379:Mice; D008957:Models, Genetic; D009132:Muscles / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D014162:Transfection
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003432:Cross-Linking Reagents; C117552:FOX-1 protein, C elegans; D005353:Fibronectins; D020033:Protein Isoforms; C455479:RBFOX1 protein, human; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C465036:Rbfox1 protein, mouse; D012097:Repressor Proteins