The Wordeman lab investigates the role that dynamic microtubules and microtubule motors play in ensuring the fidelity of chromosome segregation during cell division. Subtle changes in microtubule dynamics critically affect all aspects of mitotic spindle function. Often small changes in microtubule assembly dynamics will promote chromosome instability and tumorigenesis over time. Mitotic motors use the energy of ATP hydrolysis to organize and modulate dynamic microtubules within the cell. In this way motors facilitate the assembly of the mitotic spindle, assist in translocating chromosomes, and position the mitotic spindle within the cell in the correct orientation.

One unusual class of kinesin-related motor proteins that we study is the Kinesin-13 Family or Microtubule Depolymerizing Kinesins. This family comprises 3 unique genes in mammals: Kif2A, Kif2B and Kif2C/MCAK or Mitotic Centromere Associated Kinesin. Our research utilizes structural and molecular mutational analysis, gene depletions and live imaging to understand the functions of these proteins in living cells, especially during cell divieion (mitosis). Many of the kinesin motors we study operate at the nexus between microtubule dynamics and microtubule-dependent force generation because they control microtubule length and assembly dynamics in in conjunction with their activites as motors and force generating molecules.

Click here to see MCAK protein in a living mitotic cell.

MCAK tracking on the ends of astral microtubules regulates their length as depletion of MCAK protein results in long astral microtubules and a startling loss of spindle position as described in Kathleen Rankin's cover paper in the Journal of Cell Biology (2010) 190:35-43.

This phenomenon is the subject of a JCB biosights profile.

Click here to see a movie showing a rocking spindle in a live MCAK-depleted cell.

In addition to investigating the cellular function of MCAK which involves the regulation of microtubule length and error correction during chromosome segregation. We also study the behavior and properties of single MCAK molecules using Total Internal Reflection Fluorescence (TIRF) microscopy in vitro.

Click here to see GFP-MCAK protein depolymerizing microtubules.

We have also investigated the role of Kif18A in chromosome congression. This kinesin is a member of the kinesin-8  family. In mammalian cells this kinesin controls microtubule length by supressing microtubule growth and disassembly, rather than depolymerizing microtubules as has been shown for MCAK. Kif18A is a highly processive kinesin which can walk along spindle microtubules for many microns without detaching. This allows the motor to reach the plus-end of the microtubule and modulate its assembly properties. In spindles Kif18A uses this activity to restrict the movement of chromosomes to the midzone of the spindle. Loss of this protein allows the chromosomes to meander out of the spindle midzone and risk improper segregation during cell division. This loss of proper midzone chromosome localization in dividing cells is shown in the following images from Jason Stumpff's publicationsJason is now a professor at the University of Vermont.

Check out our papers on PubMed for more information and recent publications from our lab.