A new mechanism controlling kinetochore–microtubule interactions revealed by comparison of two dynein-targeting components: SPDL-1 and the Rod/Zwilch/Zw10 complex

  1. Reto Gassmann1,
  2. Anthony Essex1,9,
  3. Jia-Sheng Hu1,5,9,
  4. Paul S. Maddox1,6,
  5. Fumio Motegi2,7,
  6. Asako Sugimoto2,
  7. Sean M. O’Rourke3,
  8. Bruce Bowerman3,
  9. Ian McLeod4,
  10. John R. Yates III4,
  11. Karen Oegema1,
  12. Iain M. Cheeseman1,8, and
  13. Arshad Desai1,10
  1. 1 Ludwig Institute for Cancer Research/Dept of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA;
  2. 2 Laboratory for Developmental Genomics, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;
  3. 3 Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA;
  4. 4 Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA

  1. ↵9 These authors contributed equally to this work.

Abstract

Chromosome segregation requires stable bipolar attachments of spindle microtubules to kinetochores. The dynein/dynactin motor complex localizes transiently to kinetochores and is implicated in chromosome segregation, but its role remains poorly understood. Here, we use the Caenorhabditis elegans embryo to investigate the function of kinetochore dynein by analyzing the Rod/Zwilch/Zw10 (RZZ) complex and the associated coiled-coil protein SPDL-1. Both components are essential for Mad2 targeting to kinetochores and spindle checkpoint activation. RZZ complex inhibition, which abolishes both SPDL-1 and dynein/dynactin targeting to kinetochores, slows but does not prevent the formation of load-bearing kinetochore–microtubule attachments and reduces the fidelity of chromosome segregation. Surprisingly, inhibition of SPDL-1, which abolishes dynein/dynactin targeting to kinetochores without perturbing RZZ complex localization, prevents the formation of load-bearing attachments during most of prometaphase and results in extensive chromosome missegregation. Coinhibition of SPDL-1 along with the RZZ complex reduces the phenotypic severity to that observed following RZZ complex inhibition alone. We propose that the RZZ complex can inhibit the formation of load-bearing attachments and that this activity of the RZZ complex is normally controlled by dynein/dynactin localized via SPDL-1. This mechanism could coordinate the hand-off from initial weak dynein-mediated lateral attachments, which help orient kinetochores and enhance their ability to capture microtubules, to strong end-coupled attachments that drive chromosome segregation.

Keywords

Footnotes

  • ↵5 Present addresses:

    ↵5 Department of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, Irvine, CA 92697, USA;

  • ↵6 Institute for Research in Immunology and Cancer, Department of Pathology and Cell Biology, University of Montreal, Montreal, Quebec H3C 3J7, Canada;

  • ↵7 Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, MD 21218, USA;

  • ↵8 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

  • ↵10 Corresponding author.

    ↵10 E-MAIL abdesai{at}ucsd.edu; FAX (858)-534-7750.

  • Supplemental material is available at http://www.genesdev.org.

  • Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1687508.

    • Received April 22, 2008.
    • Accepted July 18, 2008.
| Table of Contents

This Article

  1. doi: 10.1101/gad.1687508 Genes & Dev. 22: 2385-2399 Copyright © 2008, Cold Spring Harbor Laboratory Press

Article Category

Share

Current Issue

  1. March 1, 2024, 38 (5-6)
  1. Current Issue
  1. Alert me to new issues of G&D

Life Science Alliance