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PMID: 22559944 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation.

Cell ·Vol. 149 ·No. 4 ·2012-05-11 ·Pages 923-35

Charrier C, Joshi K, Coutinho-Budd J, Kim JE, Lambert N, de Marchena J, Jin WL, Vanderhaeghen P, Ghosh A, Sassa T, Polleux F

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.

MeSH Terms
Animals Brain/cytology,embryology Cell Movement Dendritic Spines/metabolism Evolution, Molecular GTPase-Activating Proteins/genetics Gene Duplication Humans Mice Molecular Sequence Data Neurons/cytology,metabolism Protein Structure, Tertiary Segmental Duplications, Genomic Species Specificity
Chemicals
GTPase-Activating Proteins SRGAP2 protein, human
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Charrier Cécile
Department of Cell Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Joshi Kaumudi
Coutinho-Budd Jaeda
Kim Ji-Eun
Lambert Nelle
de Marchena Jacqueline
Jin Wei-Lin
Vanderhaeghen Pierre
Ghosh Anirvan
Sassa Takayuki
Polleux Franck
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.03.034
Published
2012-05-11
Epub
2012-00-03
Pages
923-35
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3357949
Subset
IM
Grants
NINDS NIH HHS · F31 NS068038 · United States
NINDS NIH HHS · F31NS068038 · United States
NINDS NIH HHS · R01 NS067557 · United States
NINDS NIH HHS · R01NS067557 · United States
NINDS NIH HHS · F31NS061610 · United States
NINDS NIH HHS · F31 NS061610 · United States
Databases
GENBANK
BC112927, BC132874
Corrections
CommentIn
PMID: 22579279
CommentIn
PMID: 22673161
External Links
PubMed source DOI: 10.1016/j.cell.2012.03.034 PMC Full Text View journal details
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