Nova-1 Regulates Neuron-Specific Alternative Splicing and Is Essential for Neuronal Viability

Neuron. 2000 Feb;25(2):359-71. doi: 10.1016/s0896-6273(00)80900-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing / physiology*
  • Animals
  • Antigens, Neoplasm*
  • Apoptosis / genetics
  • Brain Chemistry / genetics
  • Brain Stem / cytology
  • Brain Stem / embryology
  • Cell Survival / genetics
  • Exons / genetics
  • Gene Deletion
  • Gene Expression Regulation, Developmental
  • Genotype
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Neurons / chemistry
  • Motor Neurons / cytology*
  • Motor Neurons / physiology*
  • Nerve Tissue Proteins*
  • Protein Binding / genetics
  • RNA Precursors / genetics
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism
  • Receptors, Glycine / genetics
  • Receptors, Glycine / metabolism
  • Ribonucleoproteins / genetics*
  • Ribonucleoproteins / metabolism
  • Spinal Cord / cytology
  • Spinal Cord / embryology

Substances

  • Antigens, Neoplasm
  • Nerve Tissue Proteins
  • Nova antigen
  • RNA Precursors
  • RNA-Binding Proteins
  • Receptors, GABA-A
  • Receptors, Glycine
  • Ribonucleoproteins