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Evolutionary expansion and anatomical specialization of synapse proteome complexity


Understanding the origins and evolution of synapses may provide insight into species diversity and the organization of the brain. Using comparative proteomics and genomics, we examined the evolution of the postsynaptic density (PSD) and membrane-associated guanylate kinase (MAGUK)-associated signaling complexes (MASCs) that underlie learning and memory. PSD and MASC orthologs found in yeast carry out basic cellular functions to regulate protein synthesis and structural plasticity. We observed marked changes in signaling complexity at the yeast-metazoan and invertebrate-vertebrate boundaries, with an expansion of key synaptic components, notably receptors, adhesion/cytoskeletal proteins and scaffold proteins. A proteomic comparison of Drosophila and mouse MASCs revealed species-specific adaptation with greater signaling complexity in mouse. Although synaptic components were conserved amongst diverse vertebrate species, mapping mRNA and protein expression in the mouse brain showed that vertebrate-specific components preferentially contributed to differences between brain regions. We propose that the evolution of synapse complexity around a core proto-synapse has contributed to invertebrate-vertebrate differences and to brain specialization.

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Figure 1: Comparison of PSD and MASC homologs and expansion of selected functional groups of genes.
Figure 2: Proteomic analysis of the Drosophila MASC.
Figure 3: Variation in expression patterns in mouse brain regions.
Figure 4: Summary of relationships of synaptic proteome evolution with neuronal number, behavior and expression patterns.


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We thank L. Hansen and L. Valor for assistance with array data, M. Marshall and K. Page for literature curation, A.J. Vilella, members of Genes to Cognition program for discussions and J.V. Turner for editorial assistance. This work was supported by the Wellcome Trust (C.N.G.A., J.D.A., R.D.E., M.O.C., M.D.R.C., J.S.C. and S.G.N.G.), the Medical Research Council (A.J.P. and R.D.E.), GlaxoSmithKline (B.R.M.), Edinburgh University and the e-Science Institute (J.D.A.), and the European Molecular Biology Organization (A.B.).

Author information

Authors and Affiliations



R.D.E. conducted bioinformatic analysis of MASCs/PSDs and fMASCs. A.J.P. carried out bioinformatic and statistical analyses of MASCs/PSDs, fMASCs and expression datasets. C.N.G.A. and C.A.V. performed RNA and protein expression studies. B.R.M., A.B., M.O.C. and J.S.C. conducted fly proteomic studies. M.D.R.C. provided informatic support. R.D.E., A.J.P., C.G.N.A., J.D.A. and S.G.N.G. interpreted the results and prepared the manuscript. S.G.N.G. conceived and supervised the project.

Corresponding author

Correspondence to Seth G N Grant.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Methods (PDF 1558 kb)

Supplementary Table 1

NRC/MASC orthologs across 19 species. (XLS 172 kb)

Supplementary Table 2

PSD orthologs across 19 species. (XLS 484 kb)

Supplementary Table 3

Function of PSD/MASC orthologs in yeast. (XLS 105 kb)

Supplementary Table 4

PFAM domains present in PSD/MASC genes and their orthologs. (XLS 82 kb)

Supplementary Table 5

Composition and functional annotation of fMASC. (XLS 57 kb)

Supplementary Table 6

fMASC orthologs across 16 species. (XLS 164 kb)

Supplementary Table 7

Composition and functional annotation of mMASC/mPSD. (XLS 111 kb)

Supplementary Table 8

Anatomical expression patterns of synaptic proteins. (XLS 48 kb)

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Emes, R., Pocklington, A., Anderson, C. et al. Evolutionary expansion and anatomical specialization of synapse proteome complexity. Nat Neurosci 11, 799–806 (2008).

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