title: Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability.
abstract: We have combined genetic and biochemical approaches to analyze the function of the RNA-binding protein Nova-1, the paraneoplastic opsoclonus-myoclonus ataxia (POMA) antigen. Nova-1 null mice die postnatally from a motor deficit associated with apoptotic death of spinal and brainstem neurons. Nova-1 null mice show specific splicing defects in two inhibitory receptor pre-mRNAs, glycine alpha2 exon 3A (GlyRalpha2 E3A) and GABA(A) exon gamma2L. Nova protein in brain extracts specifically bound to a previously identified GlyRalpha2 intronic (UCAUY)3 Nova target sequence, and Nova-1 acted directly on this element to increase E3A splicing in cotransfection assays. We conclude that Nova-1 binds RNA in a sequence-specific manner to regulate neuronal pre-mRNA alternative splicing; the defect in splicing in Nova-1 null mice provides a model for understanding the motor dysfunction in POMA.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York 10021, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Jensen
authors.forename: B K
authors.initials: BK
authors.lastname: Dredge
authors.forename: G
authors.initials: G
authors.lastname: Stefani
authors.forename: R
authors.initials: R
authors.lastname: Zhong
authors.forename: R J
authors.initials: RJ
authors.lastname: Buckanovich
authors.forename: H J
authors.initials: HJ
authors.lastname: Okano
authors.forename: Y Y
authors.initials: YY
authors.lastname: Yang
authors.forename: R B
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000235:genetics; D001923:Brain Chemistry / Q000235:genetics; D001933:Brain Stem / Q000166:cytology / Q000196:embryology; D002470:Cell Survival / Q000235:genetics; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000737:chemistry / Q000166:cytology* / Q000502:physiology*; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D011485:Protein Binding / Q000235:genetics; D012322:RNA Precursors / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology
chemical_list: D000951:Antigens, Neoplasm; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D012261:Ribonucleoproteins