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J. Biol. Chem., Vol. 279, Issue 24, 25703-25710, June 11, 2004

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Centrin Gene Disruption Impairs Stage-specific Basal Body Duplication and Cell Cycle Progression in Leishmania^*

Angamuthu Selvapandiyan, Alain Debrabant, Robert Duncan, Jacqueline Muller, Poonam Salotra¶, Gannavaram Sreenivas¶, Jeffrey L. Salisbury||, and Hira L. Nakhasi**

From the Laboratory of Bacterial, Parasitic and Unconventional Agents, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review and the Laboratory of Vector Borne Diseases, Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, the ^¶Institute of Pathology (Indian Council of Medical Research), Safdarjung Hospital, New Delhi 110 029, India, and the ^||Tumor Biology Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Centrin is a calcium-binding cytoskeletal protein involved in the duplication of centrosomes in higher eukaryotes. 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 terminal deoxy uridine triphosphate nick end labeling positivity was observed in centrin mutant axenic amastigotes compared with 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.

Received for publication, March 11, 2004

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: DETTD/OBRR/CBER/FDA, Bldg. 29, Rm. 222, 8800 Rockville Pike, Bethesda, MD 20892. Tel.: 301-496-2205; Fax: 301-480-7928; E-mail: nakhasi{at}cber.fda.gov.

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