Nova-1 regulates neuron-specific alternative splicing and is essential forneuronal viability

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 defic it associated with apoptotic death of spinal and brainstem neurons. Nova-1 null mice show specific splicing defects in two inhibitory receptor pre-mRN As, glycine alpha 2 exon 3A (GlyR alpha 2 E3A) and GABA(A) exon gamma 2L. N ova protein in brain extracts specifically bound to a previously identified GlyR alpha 2 intronic (UCAUY)(3) Nova target sequence, and Nova-1 acted di rectly on this element to increase E3A splicing in cotransfection assays. W e 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 nu ll mice provides a model for understanding the motor dysfunction in POMA.