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Franck PolleuxNovel molecular mechanisms underlying mouse and human cortical development : srGAP2 controls neuronal migration, neurite formation and spine morphogenesis through its non-canonical F-BAR domain.

Abstract :

We are interested in identifying some of the molecular basis underlying human brain speciation.
Gene duplication is one of the major force driving evolutionary changes and a key mechanism in the emergence of new biological processes. Recent whole genome assessment of gene copy number comparing human to five non-human primate species has found a surprisingly limited number of genes (136) that have undergone specific gene duplication in the human lineage. Interestingly, many of these genes such as Pak2, Rock1, Arhgef6, Cesrl2 are highly enriched in the brain (Sikela, 2006). We found for the first time that one of these genes called srGAP2 plays a unique role in the control of neuronal migration, neuronal morphogenesis as well as dendritic spine formation during cortical development.
Our results show that SRGAP2 controls several key aspects of cortical development through its F-BAR domain. Recently identified F-BAR domains are thought to control endocytosis in coordination with dynamins by regulating membrane curvature and tubulation. Interestingly, several F-BAR containing proteins have been implicated in neurological disorders including mental retardation. However, the in vivo function of F-BAR domain containing proteins is currently unknown. We report that SRGAP2, is highly expressed in the developing mouse brain including the cerebral cortex where it controls neuronal migration and morphology through a non-canonical F-BAR domain which promotes membrane protrusion and filopodia formation. Using ex utero cortical electroporation coupled with slice culture, we found that knockdown of SRGAP2 by shRNA increased the rate of initiation of neuronal migration while overexpression of FNBP2 increases self-renewal of radial glial progenitors and also inhibits neuronal migration. These effects are largely dependent on the F-BAR domain which is both necessary and sufficient for the effects of SRGAP2 on neuronal migration and neuronal morphogenesis. Surprisingly, one of the duplication event found in humans has only duplicated the coding sequence corresponding to the F-BAR domain of srGAP2. We are currently ‘humanizing’ the mouse genome for this duplication event in order to assess its developmental function.       

Selected publications

Guerrier S, Polleux F.
The ups and downs of neural progenitors: Cep120 and TACCs control interkinetic nuclear migration.
Neuron. 2007 Oct 4;56(1):1-3.
PMID: 17920006 [PubMed - indexed for MEDLINE]
Barnes AP, Lilley BN, Pan YA, Plummer LJ, Powell AW, Raines AN, Sanes JR, Polleux F.
LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons.
Cell. 2007 May 4;129(3):549-63.
PMID: 17482548 [PubMed - indexed for MEDLINE]

Polleux F, Ince-Dunn G, Ghosh A.
Transcriptional regulation of vertebrate axon guidance and synapse formation.
Nat Rev Neurosci. 2007 May;8(5):331-40. Review.
PMID: 17453014 [PubMed - indexed for MEDLINE]

Jean Pierre Mothet