Nova autoregulation reveals dual functions in neuronal splicing.
The Nova family of neuron-specific RNA-binding proteins were originally identified as targets in an autoimmune neurologic disease characterized by failure of motor inhibition. Nova-1 regulates alternative splicing of pre-mRNAs encoding the inhibitory neurotransmitter receptor subunits GABA(A)Rgamma2 and GlyRalpha2 by directly binding intronic elements, resulting in enhancement of exon inclusion. Here we identify exon E4 in the Nova-1 pre-mRNA itself, encoding a phosphorylated protein domain, as an additional target of Nova-dependent splicing regulation in the mouse spinal cord. Nova binding to E4 is necessary and sufficient for Nova-dependent exon exclusion. E4 harbors five repeats of the known Nova-binding tetranucleotide YCAY and mutation of these elements destroys Nova-dependent regulation. Furthermore, swapping of the sites from Nova-1 and GABA(A)Rgamma2 indicates that the ability of Nova to enhance or repress alternative exon inclusion is dependent on the position of the Nova-binding element within the pre-mRNA. These studies demonstrate that in addition to its previously described role as a splicing activator, Nova autoregulates its own expression by acting as a splicing repressor.
Dredge
B Kate
BK
Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA.
Stefani
Giovanni
G
Engelhard
Caitlin C
CC
Darnell
Robert B
RB
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D000090682:Neuro-Oncological Ventral Antigen; D009474:Neurons / Q000502:physiology*; D017434:Protein Structure, Tertiary; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics; D018009:Receptors, Glycine / Q000235:genetics; D016415:Sequence Alignment
D000951:Antigens, Neoplasm; C439504:GLRA2 protein, human; C501173:Glra2 protein, mouse; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D011963:Receptors, GABA-A; D018009:Receptors, Glycine