Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability |
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| Authors: | Jensen K B Dredge B K Stefani G Zhong R Buckanovich R J Okano H J Yang Y Y Darnell R B |
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| Institution: | Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York 10021, USA. |
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| 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. |
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