Genetic deletion of SEPT7 reveals a cell type-specific role of septins in microtubule destabilization for the completion of cytokinesis

PLoS Genet. 2014 Aug 14;10(8):e1004558. doi: 10.1371/journal.pgen.1004558. eCollection 2014 Aug.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / genetics
  • Cytokinesis / genetics*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gastrula / growth & development
  • Humans
  • Mice
  • Microtubules / genetics*
  • Phenylurea Compounds / pharmacology
  • Pyridines / pharmacology
  • Septins / biosynthesis
  • Septins / genetics*
  • Sequence Deletion
  • Stathmin / biosynthesis
  • Stathmin / genetics*

Substances

  • Phenylurea Compounds
  • Pyridines
  • Stathmin
  • Stmn1 protein, mouse
  • Sept7 protein, mouse
  • Septins
  • N-(2-chloro-4-pyridyl)-N'-phenylurea

Grant support

This work was funded by the Deutsche Forschungsgemeinschaft Grant KO2091/1-3 to AK and MGae, Sonderforschungsbereich 738-B5 to RF and the Cluster of Excellence “From Regenerative Biology to Reconstructive Therapy” to AG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.