Unusually rapid evolution of Neuroligin-4 in mice

Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6421-6. doi: 10.1073/pnas.0801383105. Epub 2008 Apr 23.


Neuroligins (NLs) are postsynaptic cell-adhesion molecules that are implicated in humans in autism spectrum disorders because the genes encoding NL3 and NL4 are mutated in rare cases of familial autism. NLs are highly conserved evolutionarily, except that no NL4 was detected in the currently available mouse genome sequence assemblies. We now demonstrate that mice express a distant NL4 variant that rapidly evolved from other mammalian NL4 genes and that exhibits sequence variations even between different mouse strains. Despite its divergence, mouse NL4 binds neurexins and is transported into dendritic spines, suggesting that the core properties of NLs are retained in this divergent NL isoform. The selectively rapid evolution of NL4 in mice suggests that its function in the brain is under less stringent control than that of other NLs, shedding light on why its mutation in autism spectrum disorder patients is not lethal, but instead leads to a discrete developmental brain disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Biological Evolution*
  • COS Cells
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Adhesion Molecules, Neuronal
  • Chlorocebus aethiops
  • Chromosomes, Mammalian / genetics
  • Cloning, Molecular
  • Computational Biology
  • DNA, Complementary / genetics
  • Female
  • Gene Expression Regulation
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Mutation / genetics
  • Neurons / metabolism
  • Phylogeny
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Transport
  • Transfection


  • Carrier Proteins
  • Cell Adhesion Molecules, Neuronal
  • DNA, Complementary
  • Membrane Proteins
  • Nlgn4 protein, mouse
  • Protein Isoforms

Associated data

  • GENBANK/EF692521
  • GENBANK/EU350930