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Vol. 17, Issue 10, 4526-4542, October 2006

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Mammalian CLASP1 and CLASP2 Cooperate to Ensure Mitotic Fidelity by Regulating Spindle and Kinetochore Function

Ana L. Pereira^*,,, António J. Pereira^*,, Ana R.R. Maia^*,, Ksenija Drabek, C. Laura Sayas, Polla J. Hergert, Mariana Lince-Faria^*, Irina Matos^*, Cristina Duque^||, Tatiana Stepanova, Conly L. Rieder, William C. Earnshaw^¶, Niels Galjart, and Helder Maiato^*,||

*Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; Department of Cell Biology and Genetics, Erasmus Medical Centre, 3000 DR Rotterdam, The Netherlands; Division of Molecular Medicine, New York State Department of Health, Wadsworth Center, Albany, NY 12201; ^¶Wellcome Trust Centre for Cell Biology, Institute of Cell and Molecular Biology, University of Edinburgh, EH9 3JR Edinburgh, United Kingdom; and ^||Laboratory of Cell and Molecular Biology, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal

Submitted July 5, 2006; Revised August 2, 2006; Accepted August 4, 2006
Monitoring Editor: Kerry Bloom

CLASPs are widely conserved microtubule plus-end–tracking proteins with essential roles in the local regulation of microtubule dynamics. In yeast, Drosophila, and Xenopus, a single CLASP orthologue is present, which is required for mitotic spindle assembly by regulating microtubule dynamics at the kinetochore. In mammals, however, only CLASP1 has been directly implicated in cell division, despite the existence of a second paralogue, CLASP2, whose mitotic roles remain unknown. Here, we show that CLASP2 localization at kinetochores, centrosomes, and spindle throughout mitosis is remarkably similar to CLASP1, both showing fast microtubule-independent turnover rates. Strikingly, primary fibroblasts from Clasp2 knockout mice show numerous spindle and chromosome segregation defects that can be partially rescued by ectopic expression of Clasp1 or Clasp2. Moreover, chromosome segregation rates during anaphase A and B are slower in Clasp2 knockout cells, which is consistent with a role of CLASP2 in the regulation of kinetochore and spindle function. Noteworthy, cell viability/proliferation and spindle checkpoint function were not impaired in Clasp2 knockout cells, but the fidelity of mitosis was strongly compromised, leading to severe chromosomal instability in adult cells. Together, our data support that the partial redundancy of CLASPs during mitosis acts as a possible mechanism to prevent aneuploidy in mammals.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-07-0579) on August 16, 2006.

These authors contributed equally to this work.

Address correspondence to: Helder Maiato (maiato{at}ibmc.up.pt)

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