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Determine the mechanism of cytokinesis using genetics, biochemistry, and live cell imaging
A.B., Mathematics, University of California, Berkeley 1986
Ph.D., Cell Biology, University of California, San Francisco 1993,
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.
Tse YC, Werner M, Longhini KM, Labbe JC, Goldstein B, Glotzer M. (2012) RhoA activation during polarization and cytokinesis of the early Caenorhabditis elegans embryo is differentially dependent on NOP-1 and CYK-4. Mol Biol Cell. 2012 Oct;23(20):4020-31.PMCID: PMC3469517
TULIPs: Tunable, light-controlled interacting protein tags for cell biology (2012) Devin Strickland, Yuan Lin, Elizabeth Wagner, C. Matthew Hope, Josiah Zayner, Chloe Antoniou, Tobin R. Sosnick, Eric L. Weiss and Michael Glotzer. TULIPs: Tunable, light-controlled interacting protein tags for cell biology. Nature Methods, 9(4):379-8. PMCID: PMC3444151
Loria A, Longhini KM, Glotzer M. (2012) The RhoGAP Domain of CYK-4 Has an Essential Role in RhoA Activation. Curr Biol. 22(3):213-9 PMCID: PMC3285270.
Tse YC, Piekny A, Glotzer M. Anillin promotes astral microtubule-directed cortical myosin polarization. Mol Biol Cell. 2011 Sep;22(17):3165-75. Epub 2011Jul 7. PMID: 21737681; PMCID: PMC3164463.
Tse YC, Piekny A, Glotzer M. (2011) Anillin promotes astral microtubule-directed cortical myosin
polarization. Mol Biol Cell. 22:3165-75. PMID: 21737681; PMCID: PMC3164463.
Afshar K, Werner ME, Tse YC, Glotzer M*, Gönczy P.* (2010) Regulation of cortical contractility and spindle positioning by the protein phosphatase 6 PPH-6 in one-cell stage C. elegans embryos. Development. 137:237-47. PMID: 20040490; PMC2799158 (* co-corresponding authors)
Hutterer, A. Glotzer, M*, Mishima, M* (2009). Clustering of centralspindlin is essential for its accumulation to the central spindle and the midbody, Current Biology;19:2043-9. PMID: 19962307 (* co-corresponding authors)
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:e1000110. PMID:19468300; PMCID: PMC2680334.
Kieserman EK, Glotzer M, Wallingford JB. (2008) Developmental Regulation of Central Spindle Assembly and Cytokinesis during Vertebrate Embryogenesis. Curr Biol., 18 (2), 116-23.
Piekny A, Glotzer M. (2008). Anillin is a scaffold protein that links RhoA, actin, and myosin during cytokinesis. Current Biology, 18(1):30-6.
Pavicic-Kaltenbrunner V, Mishima M, Glotzer M. (2007) Cooperative Assembly of CYK-4/MgcRacGAP and ZEN-4/MKLP1 to Form the Centralspindlin Complex. Mol Biol Cell., 18(12):4992-5003.
Petronczki M, Glotzer M, Kraut N, Peters JM (2007). Polo-like kinase 1 triggers the initiation of cytokinesis in human cells by promoting recruitment of the RhoGEF Ect2 to the central spindle. Dev Cell. 12:713-25.
Yuce O, Piekny A, Glotzer M. (2005). An ECT2-centralspindlin complex regulates the localization and function of RhoA. J Cell Biol. 170:571-82.
Mishima, M, Pavicic, V, Grüneberg, U, Nigg, E., and Glotzer M. (2004). Cell cycle regulation of central spindle assembly, Nature, 430: 909-913.
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. Developmental Cell, 4, 333-344.