An ancient duplication of exon 5 in the Snap25 gene is required for complex neuronal development/function

PLoS Genet. 2008 Nov;4(11):e1000278. doi: 10.1371/journal.pgen.1000278. Epub 2008 Nov 28.

Abstract

Alternative splicing is an evolutionary innovation to create functionally diverse proteins from a limited number of genes. SNAP-25 plays a central role in neuroexocytosis by bridging synaptic vesicles to the plasma membrane during regulated exocytosis. The SNAP-25 polypeptide is encoded by a single copy gene, but in higher vertebrates a duplication of exon 5 has resulted in two mutually exclusive splice variants, SNAP-25a and SNAP-25b. To address a potential physiological difference between the two SNAP-25 proteins, we generated gene targeted SNAP-25b deficient mouse mutants by replacing the SNAP-25b specific exon with a second SNAP-25a equivalent. Elimination of SNAP-25b expression resulted in developmental defects, spontaneous seizures, and impaired short-term synaptic plasticity. In adult mutants, morphological changes in hippocampus and drastically altered neuropeptide expression were accompanied by severe impairment of spatial learning. We conclude that the ancient exon duplication in the Snap25 gene provides additional SNAP-25-function required for complex neuronal processes in higher eukaryotes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Exons / genetics*
  • Gene Duplication*
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Neurons / metabolism
  • Neurons / physiology*
  • Neuropeptides / metabolism
  • SNARE Proteins / genetics
  • SNARE Proteins / metabolism
  • Synaptosomal-Associated Protein 25 / genetics*
  • Synaptosomal-Associated Protein 25 / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Microtubule-Associated Proteins
  • Neuropeptides
  • SNARE Proteins
  • Snap25 protein, mouse
  • Synaptosomal-Associated Protein 25
  • doublecortin protein