Matthew Savoian
The spindle is a highly dynamic microtubule-based 'lattice' fundamental to successful chromosome segregation (karyokinesis) and cytoplasmic partitioning (cytokinesis). I am interested in understanding how molecules that regulate the dynamics of different subpopulations of spindle microtubules are responsible for these processes using the Drosophila model system. My work employs high resolution live cell imaging, molecular biology and biochemistry to investigate the tissue specific regulation of microtubule dynamics between somatic cell mitosis and germline male meiosis. This comparative approach indicates that although many microtubule dynamics regulating mechanisms are conserved between the different division types, a surprising degree of functional variation and flexibility also exists.
Currently I am investigating the microtubule depolymerising kinesin-8 family protein Klp67A. We showed previously that this motor protein regulates different microtubule populations between division types, but has a conserved role in limiting bipolar spindle length and promoting proper chromosome alignment. Remarkably, we found that after the transition into anaphase, Klp67A reversed function from a microtubule destabilising enzyme to stabilising one needed for maintaining the integrity of the central spindle for cytokinesis. Identifying the mechanisms responsible for Klp67A's targeting to select microtubule populations and its mode of action is essential to understanding the basic principles of spindle morphogenesis and function.
Utilising mitotic tissue culture cells, I have determined which of Klp67A's domains are responsible for the protein's localisation and early mitotic functions. Klp67A limits spindle length and promotes chromsome alignment using its motor's catalytic activity exclusively when positioned at kinetochores, and its spindle associated pool is not involved in these events. Photobleaching studies indicate that Klp67A dynamically associates with the kinetochore as early as prophase and that this interaction does not require microtubules. However, efficient kinetochore association requires ATP hydrolysis by the catalytic motor domain. Preliminary data further indicate that kinetochore binding is sensitive to the activities of different protein kinases. Along with studying the mechanisms responsible for kinetochore and spindle localisation, I am identifying Klp67A interacting and functionally antagonising proteins. The interplay of such factors (e.g., Mini-spindles) and Klp67A's phosphorylation state may further account for the protein's role in stabilising the central spindle- an area of ongoing investigation.
Areas of interest:- Microtubule dynamics
- Spindle and kinetochore/chromatin interactions
- Bipolar- and Central- spindle morphogenesis
- RanGTP mediated microtubule nucleation
- Microtubule post-translational modifications and MAP (microtubule associated protein) binding
- Microtubule motor proteins
- mini-spindles
- klp67A
- klp59c
- orbit/mast
Dr. Matthew Savoian
Address:
Department of Genetics,
University of Cambridge,
Downing Street,
Cambridge,
CB2 3EH,
England.
Email:
ms476@
mole.bio.cam.ac.uk
Laycock JE, Savoian MS and Glover DM (2006)
Antagonistic activities of Klp10A and Orbit regulate spindle length, bipolarity and function in vivo.
Journal of Cell Science 119: 2354-2361
Petretti C, Savoian M, Montembault E, Glover DM, Prigent C and Giet R (2006)
The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation.
EMBO Reports 7: 418-424
Back to the list of current members.
Information about former members of the Glover group is available.