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PMID:22559944

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Citation

Charrier, C, Joshi, K, Coutinho-Budd, J, Kim, JE, Lambert, N, de Marchena, J, Jin, WL, Vanderhaeghen, P, Ghosh, A, Sassa, T and Polleux, F (2012) Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell 149:923-35

Abstract

Structural genomic variations represent a major driving force of evolution, and a burst of large segmental gene duplications occurred in the human lineage during its separation from nonhuman primates. SRGAP2, a gene recently implicated in neocortical development, has undergone two human-specific duplications. Here, we find that both duplications (SRGAP2B and SRGAP2C) are partial and encode a truncated F-BAR domain. SRGAP2C is expressed in the developing and adult human brain and dimerizes with ancestral SRGAP2 to inhibit its function. In the mouse neocortex, SRGAP2 promotes spine maturation and limits spine density. Expression of SRGAP2C phenocopies SRGAP2 deficiency. It underlies sustained radial migration and leads to the emergence of human-specific features, including neoteny during spine maturation and increased density of longer spines. These results suggest that inhibition of SRGAP2 function by its human-specific paralogs has contributed to the evolution of the human neocortex and plays an important role during human brain development.

Links

PubMed PMC3357949 Online version:10.1016/j.cell.2012.03.034

Keywords

Animals; Brain/cytology; Brain/embryology; Cell Movement; Dendritic Spines/metabolism; Evolution, Molecular; GTPase-Activating Proteins/genetics; Gene Duplication; Humans; Mice; Molecular Sequence Data; Neurons/cytology; Neurons/metabolism; Protein Structure, Tertiary; Segmental Duplications, Genomic; Species Specificity

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SRGP2

located_in

GO:0044327: dendritic spine head

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SRGP2

involved_in

GO:2001223: negative regulation of neuron migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRGP2

involved_in

GO:0046847: filopodium assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRGP2

involved_in

GO:0060996: dendritic spine development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRGP2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P0DJJ0

F

Seeded From UniProt

complete

HUMAN:SRG2C

involved_in

GO:0021816: extension of a leading process involved in cell motility in cerebral cortex radial glia guided migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRG2C

enables

GO:0042803: protein homodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P0DJJ0

F

Seeded From UniProt

complete

HUMAN:SRG2C

involved_in

GO:0051490: negative regulation of filopodium assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRG2C

involved_in

GO:2001224: positive regulation of neuron migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRG2C

involved_in

GO:0061000: negative regulation of dendritic spine development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRG2C

enables

GO:0046982: protein heterodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75044

F

Seeded From UniProt

complete

MOUSE:SRGP2

located_in

GO:0045211: postsynaptic membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SRGP2

located_in

GO:0014069: postsynaptic density

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SRGP2

involved_in

GO:0060996: dendritic spine development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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