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Papers In Press, published online ahead of print April 14, 2004
DETTD/OBRR/CBER, FDA, Bethesda, MD 20892
Corresponding Author: Nakhasi{at}cber.fda.gov
Centrin is a calcium binding cytoskeletal protein involved in duplication of centrosomes in higher eukaryotes. In order to explore the role of centrin in the protozoan parasite Leishmania, we created Leishmania deficient in the centrin gene (LdCEN). Remarkably, centrin null mutants (LdCEN-/-) showed selective growth arrest as axenic amastigotes but not as promastigotes. Flow cytometry analysis confirmed that the mutant axenic amastigotes have a cell cycle arrest at the G2/M stage. The axenic amastigotes also showed failure of basal body duplication and failure of cytokinesis resulting in multinucleated ‘large’ cells. Increased TUNEL positivity was observed in centrin mutant axenic amastigotes compared to wild type cells suggesting the activation of a programmed cell death pathway. Growth of LdCEN-/- amastigotes in infected macrophages in vitro was inhibited and also resulted in large multinucleated parasites. Normal basal body duplication and cell division in the LdCEN knockout promastigote is unique and surprising. Further, this is the first report where disruption of a centrin gene displays stage specific/cell type specific failure in cell division in a eukaryote. The centrin null mutant defective in amastigote growth could be useful as a vaccine candidate against leishmaniasis.
J. Biol. Chem, 10.1074/jbc.M402794200
Submitted on March 11, 2004
Revised on April 14, 2004
Accepted on April 14, 2004
Centrin gene disruption impairs stage specific basal body duplication and cell cycle progression in Leishmaniac
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