title: Lack of Diaph3 relaxes the spindle checkpoint causing the loss of neural progenitors.
abstract: The diaphanous homologue Diaph3 (aka mDia2) is a major regulator of actin cytoskeleton. Loss of Diaph3 has been constantly associated with cytokinesis failure ascribed to impaired accumulation of actin in the cleavage furrow. Here we report that Diaph3 is required before cell fission, to ensure the accurate segregation of chromosomes. Inactivation of the Diaph3 gene causes a massive loss of cortical progenitor cells, with subsequent depletion of intermediate progenitors and neurons, and results in microcephaly. In embryonic brain extracts, Diaph3 co-immunoprecipitates with BubR1, a key regulator of the spindle assembly checkpoint (SAC). Diaph3-deficient cortical progenitors have decreased levels of BubR1 and fail to properly activate the SAC. Hence, they bypass mitotic arrest and embark on anaphase in spite of incorrect chromosome segregation, generating aneuploidy. Our data identify Diaph3 as a major guard of cortical progenitors, unravel novel functions of Diaphanous formins and add insights into the pathobiology of microcephaly.
authors.affiliation: Developmental Neurobiology Unit, Université catholique de Louvain, Institute of Neuroscience, Avenue Mounier 73, Box B1.73.16, Brussels 1200, Belgium.|Developmental Neurobiology Unit, WELBIO, Institute of Neuroscience, Avenue Mounier B1.73.16, Brussels 1200, Belgium.
authors.forename: Devid
authors.initials: D
authors.lastname: Damiani
authors.affiliation: Developmental Neurobiology Unit, Université catholique de Louvain, Institute of Neuroscience, Avenue Mounier 73, Box B1.73.16, Brussels 1200, Belgium.|Developmental Neurobiology Unit, WELBIO, Institute of Neuroscience, Avenue Mounier B1.73.16, Brussels 1200, Belgium.
authors.forename: André M
authors.initials: AM
authors.lastname: Goffinet
authors.affiliation: Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, 333 Bostwick Avenue N.E., Grand Rapids, Michigan 49503, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Alberts
authors.affiliation: Developmental Neurobiology Unit, Université catholique de Louvain, Institute of Neuroscience, Avenue Mounier 73, Box B1.73.16, Brussels 1200, Belgium.
authors.forename: Fadel
authors.initials: F
authors.lastname: Tissir
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D000080865:Formins; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology; D009154:Mutation; D009252:NADPH Dehydrogenase / Q000378:metabolism*; D058953:Neural Stem Cells / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; C484571:DIAPH3 protein, human; D000080865:Formins; D008869:Microtubule-Associated Proteins; C508552:Dia2 protein, mouse; D009252:NADPH Dehydrogenase; D017346:Protein Serine-Threonine Kinases