title: Genetic deletion of SEPT7 reveals a cell type-specific role of septins in microtubule destabilization for the completion of cytokinesis.
abstract: Cytokinesis terminates mitosis, resulting in separation of the two sister cells. Septins, a conserved family of GTP-binding cytoskeletal proteins, are an absolute requirement for cytokinesis in budding yeast. We demonstrate that septin-dependence of mammalian cytokinesis differs greatly between cell types: genetic loss of the pivotal septin subunit SEPT7 in vivo reveals that septins are indispensable for cytokinesis in fibroblasts, but expendable in cells of the hematopoietic system. SEPT7-deficient mouse embryos fail to gastrulate, and septin-deficient fibroblasts exhibit pleiotropic defects in the major cytokinetic machinery, including hyperacetylation/stabilization of microtubules and stalled midbody abscission, leading to constitutive multinucleation. We identified the microtubule depolymerizing protein stathmin as a key molecule aiding in septin-independent cytokinesis, demonstrated that stathmin supplementation is sufficient to override cytokinesis failure in SEPT7-null fibroblasts, and that knockdown of stathmin makes proliferation of a hematopoietic cell line sensitive to the septin inhibitor forchlorfenuron. Identification of septin-independent cytokinesis in the hematopoietic system could serve as a key to identify solid tumor-specific molecular targets for inhibition of cell proliferation.
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Menon
authors.affiliation: Department of Molecular Biology, Division of Biological Science, Nagoya University Graduate School of Science, Furo, Chikusa, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sawada
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Anuhar
authors.initials: A
authors.lastname: Chaturvedi
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Pooja
authors.initials: P
authors.lastname: Mishra
authors.affiliation: Institute of Molecular Biology, Hannover Medical School, Hannover, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Schuster-Gossler
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Galla
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.affiliation: Institute of Molecular Biology, Hannover Medical School, Hannover, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Gossler
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Förster
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kotlyarov
authors.affiliation: Department of Molecular Biology, Division of Biological Science, Nagoya University Graduate School of Science, Furo, Chikusa, Nagoya, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D048749:Cytokinesis / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005775:Gastrula / Q000254:growth & development; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000235:genetics*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D058112:Septins / Q000096:biosynthesis / Q000235:genetics*; D017384:Sequence Deletion; D050777:Stathmin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; D050777:Stathmin; C493994:Stmn1 protein, mouse; C512895:Sept7 protein, mouse; D058112:Septins; C116093:N-(2-chloro-4-pyridyl)-N'-phenylurea