ISDN2012_0241: Developmental and evolutionary functions of a human‐specific gene duplication of srGAP2 during brain development

Cécile Charrier 1,5, Kaumudi Joshi 1,5, Takayuki Sassa 2,5, Jaeda Coutinho-Budd 3, Nelle Lambert 4, Pierre Vanderhaegen 4, Franck Polleux 1,∗ 1 The Scripps Research Institute, Dorris Neuroscience Center, Department of Cell Biology, La Jolla, CA 92037USA 2 Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan 3 Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA 4 IRIBHM Université Libre de Bruxelles, Brussels, Belgium Large segmental gene duplication is a major driver of evolution. Recently, several lines of evidence have revealed that a burst of gene duplications occurred in the human lineage during its separation from non-human primates. Previous analyses showed that an unusually high proportion of these human-specific duplications affect genes expressed during brain development, however their evolutionary significance and biological functions are currently unknown. We found that the gene SRGAP2 was duplicated twice in the human lineage. We determined the copy number, genomic organization, sequence and expression of the human-specific copies of SRGAP2. The ancestral SRGAP2 protein has three functional domains: a F-BAR domain capable of membrane-deformation, a Rac1-specific GAP domain and a SH3 domain. In the developing mouse cortex, SRGAP2 promotes neurite branching via the ability of its F-BAR domain to induce filopodia. Here we demonstrate that the human-specific copy SRGAP2p12 expresses a truncated form of the ancestral SRGAP2 gene encoding most of the F-BAR domain. Interestingly, SRGAP2p12 fails to induce filopodial protrusions in COS7 cells but retains its ability to dimerize with full length SRGAP2 and thereby negatively modulates the ability of the ancestral SRGAP2 protein to induce filopodia. Furthermore, when expressed in embryonic cortical neurons in vivo, SRGAP2p12 phenocopies the loss of SRGAP2 by reducing neuronal branching and promoting migration. Importantly, we describe a novel function for SRGAP2 which is critical for the proper maturation of dendritic spine morphology. SRGAP2 over-expression promotes spine growth and maturation, whereas SRGAP2p12 phenocopies geneticor shRNA-mediated loss-of-function of SRGAP2 which slows down the rate of maturation of spine morphology and leads to increased adult spine density in vivo. Our results suggest that SRGAP2 gene duplication might have provided the Homo lineage with a distinct evolutionary advantage at least in part by regulating the rate of synaptic maturation. Supported by NIH grant R01-NS067557 and ADI funding.