title: Rac-GTPases Regulate Microtubule Stability and Axon Growth of Cortical GABAergic Interneurons.
abstract: Cortical interneurons are characterized by extraordinary functional and morphological diversity. Although tremendous progress has been made in uncovering molecular and cellular mechanisms implicated in interneuron generation and function, several questions still remain open. Rho-GTPases have been implicated as intracellular mediators of numerous developmental processes such as cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. Specifically in cortical interneurons, we have recently shown a cell-autonomous and stage-specific requirement for Rac1 activity within proliferating interneuron precursors. Conditional ablation of Rac1 in the medial ganglionic eminence leads to a 50% reduction of GABAergic interneurons in the postnatal cortex. Here we examine the additional role of Rac3 by analyzing Rac1/Rac3 double-mutant mice. We show that in the absence of both Rac proteins, the embryonic migration of medial ganglionic eminence-derived interneurons is further impaired. Postnatally, double-mutant mice display a dramatic loss of cortical interneurons. In addition, Rac1/Rac3-deficient interneurons show gross cytoskeletal defects in vitro, with the length of their leading processes significantly reduced and a clear multipolar morphology. We propose that in the absence of Rac1/Rac3, cortical interneurons fail to migrate tangentially towards the pallium due to defects in actin and microtubule cytoskeletal dynamics.
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion, Greece Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Simona
authors.initials: S
authors.lastname: Tivodar
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion, Greece Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kalemaki
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion, Greece Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Zouzana
authors.initials: Z
authors.lastname: Kounoupa
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion, Greece Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion, Greece Current Address: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Vidaki
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion, Greece Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Theodorakis
authors.affiliation: Division of Molecular Neurobiology, Medical Research Council, National Institute for Medical Research, London, UK.
authors.forename: Myrto
authors.initials: M
authors.lastname: Denaxa
authors.affiliation: Wolfson Institute for Biomedical Research and Department of Cell and Developmental Biology, University College London, UK.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Kessaris
authors.affiliation: Cell Adhesion Unit, Dibit, San Raffaele Scientific Institute, 20132 Milano, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: de Curtis
authors.affiliation: Division of Molecular Neurobiology, Medical Research Council, National Institute for Medical Research, London, UK.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Pachnis
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion, Greece Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Domna
authors.initials: D
authors.lastname: Karagogeos
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D002453:Cell Cycle / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007395:Interneurons / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008473:Median Eminence / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D011247:Pregnancy; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D008164:Luminescent Proteins; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D050257:Tubulin Modulators; C498771:Rac3 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D017239:Paclitaxel
keywords: Rho-GTPases; cortical development; cytoskeleton; medial ganglionic eminence