Michael Glotzer
Research Summary / Selected Publications
Cytokinesis is mediated by an actin-based contractile ring that is attached to the overlying cell membrane. Cytokinesis is highly regulated in time and space. The contractile ring assembles in the cell cortex after anaphase onset at a site midway between the two poles of the mitotic spindle thereby ensuring that the two sets of chromosomes are equally partitioned into the two daughter cells. We are using the nematode C. elegans and cultured human cells as model systems to dissect this complex process. We are using a combination of forward and reverse genetics, biochemistry, and live cell imaging to address the following unsolved problems: How is the cleavage furrow positioned? How does the contractile ring assemble and function? How does the central spindle assemble and function? How is completion of cytokinesis achieved?
We are particularly interested in the assembly and function of the central spindle. Central spindle assembly begins at the metaphase to anaphase transition, when chromosomes move polewards on shrinking kinetochore microtubules. At this time, non-kinetochore spindle microtubules become bundled to form the central spindle. We discovered an evolutionarily conserved protein complex, centralspindlin, consisting of a Rho family GAP, CYK-4, and a kinesin like protein, ZEN-4, that is directly involved in central spindle assembly. The central spindle is essential for completion of cytokinesis and it also regulates cleavage furrow formation. We want to understand in mechanistic terms how this motor/RhoGAP complex functions to coordinate central spindle assembly and how it regulates early and late events in cytokinesis.
In C. elegans embryos, cleavage furrow formation requires either the central spindle or astral microtubules. These two supramolecular structures appear to regulate furrow formation by distinct molecular mechanisms that converge at the GTPase RhoA. We will identify the mechanisms that lead to local activation of RhoA.
Cytokinesis is mediated by an actin-based contractile ring that is attached to the overlying cell membrane. Cytokinesis is highly regulated in time and space. The contractile ring assembles in the cell cortex after anaphase onset at a site midway between the two poles of the mitotic spindle thereby ensuring that the two sets of chromosomes are equally partitioned into the two daughter cells. We are using the nematode C. elegans and cultured human cells as model systems to dissect this complex process. We are using a combination of forward and reverse genetics, biochemistry, and live cell imaging to address the following unsolved problems: How is the cleavage furrow positioned? How does the contractile ring assemble and function? How does the central spindle assemble and function? How is completion of cytokinesis achieved?
We are particularly interested in the assembly and function of the central spindle. Central spindle assembly begins at the metaphase to anaphase transition, when chromosomes move polewards on shrinking kinetochore microtubules. At this time, non-kinetochore spindle microtubules become bundled to form the central spindle. We discovered an evolutionarily conserved protein complex, centralspindlin, consisting of a Rho family GAP, CYK-4, and a kinesin like protein, ZEN-4, that is directly involved in central...
Wolfe BA, Takaki T, Petronczki M, Glotzer M. (2009) Polo-like kinase 1 directs assembly of the HsCyk-4 RhoGAP/Ect2 RhoGEF complex to initiate cleavage furrow formation.
PLoS Biol. 7(5):e1000110. PLOS Biology
Glotzer, M. (2009) The 3Ms of central spindle assembly: microtubules, motors and MAPs. Nature Reviews Molecular Cellular Biology, 10:9-20 Nature Reviews
Piekny AJ, Glotzer M. 2008 Anillin is a scaffold protein that links RhoA, actin, and myosin during cytokinesis. Curr Biol. 18:30-6. PubMed
Pavicic-Kaltenbrunner, V., Mishima, M., and M. Glotzer 2007. Cooperative Assembly of CYK-4/MgcRacGAP and ZEN-4/MKLP1 to Form the Centralspindlin Complex Mol Biol Cell. 2007 Dec;18(12):4992-5003 PubMed
Werner, M., E. Munro, and M. Glotzer. 2007. Astral signals spatially bias cortical Myosin recruitment to break symmetry and promote cytokinesis. Curr Biol. 17:1286-1297. PubMed
Petronczki, M., M. Glotzer, N. Kraut, and J. M. Peters. 2007. Polo- kinase 1 triggers the initiation of cytokinesis in human cells by promoting recruitment of the RhoGEF Ect2 to the central spindle. Dev Cell. 12:713-725. PubMed
Guse, A., M. Mishima, and M. Glotzer. 2005. Phosphorylation of ZEN-4/MKLP1 by Aurora B Regulates Completion of Cytokinesis. Curr Biol. 15:778-786.
PubMed
Yuce O, Piekny A, Glotzer M. (2005). An ECT2-centralspindlin complex regulates the localization and function of RhoA. J Cell Biol. 170:571-82. PubMed
Hizlan, D., M. Mishima, P. Tittmann, H. Gross, M. Glotzer, and A. Hoenger. 2006. Structural analysis of the ZEN-4/CeMKLP1 motor domain and its interaction with microtubules. J Struct Biol. 153:73-84. PubMed
Glotzer, M. (2005). "The molecular requirements for cytokinesis." Science 307: 1735-9. Full Text
Mishima, M., Pavicic, V., Gruneberg, U., Nigg, E. A. and Glotzer, M. (2004). "Cell cycle regulation of central spindle assembly." Nature 430: 908-13. PubMed
Dechant, R. and Glotzer, M. (2003). "Centrosome Separation and Central Spindle Assembly Act in Redundant Pathways that Regulate Microtubule Density and Trigger Cleavage Furrow Formation." Dev Cell 4: 333-44. PubMed
Romano, A., Guse, A., Krascenicova, I., Schnabel, H., Schnabel, R. and Glotzer, M. (2003). "CSC-1: a subunit of the Aurora B kinase complex that binds to the survivin-like protein BIR-1 and the incenp-like protein ICP-1." J Cell Biol 161: 229-36.
PubMed
Mishima, M., Kaitna, S. and Glotzer, M. (2002). "Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity." Dev Cell 2: 41-54.
PubMed
Glotzer, M. (2001). "Animal cell cytokinesis." Annu Rev Cell Dev Biol 17: 351-86. PubMed
Wolfe BA, Takaki T, Petronczki M, Glotzer M. (2009) Polo-like kinase 1 directs assembly of the HsCyk-4 RhoGAP/Ect2 RhoGEF complex to initiate cleavage furrow formation.
PLoS Biol. 7(5):e1000110. PLOS Biology
Glotzer, M. (2009) The 3Ms of central spindle assembly: microtubules, motors and MAPs. Nature Reviews Molecular Cellular Biology, 10:9-20 Nature Reviews
Piekny AJ, Glotzer M. 2008 Anillin is a scaffold protein that links RhoA, actin, and myosin during cytokinesis. Curr Biol. 18:30-6. PubMed
Pavicic-Kaltenbrunner, V., Mishima, M., and M. Glotzer 2007. Cooperative Assembly of CYK-4/MgcRacGAP and ZEN-4/MKLP1 to Form the Centralspindlin Complex Mol Biol Cell. 2007 Dec;18(12):4992-5003 PubMed
Werner, M., E. Munro, and M. Glotzer. 2007. Astral signals spatially bias cortical Myosin recruitment to break symmetry and promote cytokinesis. Curr Biol. 17:1286-1297. PubMed
