Unusually rapid evolution of Neuroligin-4 in mice

doi:10.1073/pnas.0801383105

Unusually rapid evolution of Neuroligin-4 in mice

Departments of ^†Neuroscience,
^§Biochemistry, and
^¶Molecular Genetics, and
^‡Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390

Contributed by Thomas C. Südhof, February 13, 2008 (received for review January 24, 2008)

Abstract

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.

Footnotes

^‖To whom correspondence should be addressed at:
Department of Neuroscience, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9111.
E-mail: thomas.sudhof{at}utsouthwestern.edu
Author contributions: T.C.S. designed research; M.F.B., J.P., S.M., and A.A.B. performed research; M.F.B., J.P., S.M., A.A.B., N.V.G., and T.C.S. analyzed data; and M.F.B., N.V.G., and T.C.S. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. EF692521 and EU350930).
This article contains supporting information online at www.pnas.org/cgi/content/full/0801383105/DCSupplemental.