Abstract
Eukaryotic cell division requires the co-ordinated assembly and disassembly of the mitotic spindle, accurate chromosome segregation and temporal control of cytokinesis to generate two daughter cells. While the absolute details of these processes differ between organisms, there are evolutionarily conserved core components common to all eukaryotic cells, whose identification will reveal the key processes that control cell division. Glycogen synthase kinase 3 (GSK-3) is a major protein kinase found throughout the eukaryotes and regulates many processes, including cell differentiation, growth, motility and apoptosis. In animals, GSK-3 associates with mitotic spindles and its inhibition causes mis-regulation of chromosome segregation. Two suppressor screens in yeast point to a more general effect of GSK-3 on cell division, however the direct role of GSK-3 in control of mitosis has not been explored outside the animal kingdom. Here we report that the Dictyostelium discoideum GSK-3 orthologue, GskA, associates with the mitotic spindle during cell division, as seen for its mammalian counterparts. Dictyostelium possesses only a single GSK-3 gene that can be deleted to eliminate all GSK-3 activity. We found that gskA-null mutants failed to elongate their mitotic spindle and were unable to divide in shaking culture, but have no chromosome segregation defect. These results suggest further conservation for the role of GSK-3 in the regulation of spindle dynamics during mitosis, but also reveal differences in the mechanisms ensuring accurate chromosome segregation.
Highlights
Glycogen synthase kinase 3 (GSK-3) is a serine-threonine protein kinase that was originally identified as a key regulator of insulin-dependent glycogen synthesis (Woodgett, 1990)
These results suggest that there may be a conserved role of GSK3 controlling spindle function in animal cells, there have been no reports of regulation of spindle dynamics or cytokinesis outside the animal taxon
We have established that GSK-3 in Dictyostelium is associated with the mitotic spindle and is required for the normal progression of mitosis
Summary
Glycogen synthase kinase 3 (GSK-3) is a serine-threonine protein kinase that was originally identified as a key regulator of insulin-dependent glycogen synthesis (Woodgett, 1990). GSK-3 has been shown to phosphorylate several microtubule-associated proteins (MAPs), including CLASP2 (Watanabe et al, 2009), Collapsin Response Mediator Proteins (CRMPs; Cole et al, 2004), adenomatous polyposis coli (APC; Zumbrunn et al, 2001), Tau (Lovestone et al, 1996), MAP2C (Sanchez et al, 2000) and MAP1B (Goold et al, 1999). In C. elegans, loss of GSK-3 interferes with mitotic spindle orientation in 4-cell stage embryos (Schlesinger et al, 1999), and in D. melanogaster, GSK-3 localizes to the centrosome (Bobinnec et al, 2006) and loss of function mutations cause aberrant mitotic spindle morphology (Wojcik, 2008) These results suggest that there may be a conserved role of GSK3 controlling spindle function in animal cells, there have been no reports of regulation of spindle dynamics or cytokinesis outside the animal taxon. In S. cerevisiae, deletion of one of the four yeast GSK-3 orthologues, MCK1, suppressed the effects of
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