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Eukaryotic Cell, July 2006, p. 1126-1135, Vol. 5, No. 7
1535-9778/06/$08.00+0     doi:10.1128/EC.00094-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Mitogen-Activated Protein Kinase Controls Differentiation of Bloodstream Forms of Trypanosoma brucei

Debora Domenicali Pfister,¹ Gabriela Burkard,^1, Sabine Morand,^1, Christina Kunz Renggli,² Isabel Roditi,¹ and Erik Vassella^1,3*

Institut für Zellbiologie, Universität Bern, CH-3012 Bern, Switzerland,¹ Swiss Tropical Institute, CH-4002 Basel, Switzerland,² Institut für Pathologie, Universität Bern, CH-3010 Bern, Switzerland³

Received 31 March 2006/ Accepted 17 May 2006

African trypanosomes undergo differentiation in order to adapt to the mammalian host and the tsetse fly vector. To characterize the role of a mitogen-activated protein (MAP) kinase homologue, TbMAPK5, in the differentiation of Trypanosoma brucei, we constructed a knockout in procyclic (insect) forms from a differentiation-competent (pleomorphic) stock. Two independent knockout clones proliferated normally in culture and were not essential for other life cycle stages in the fly. They were also able to infect immunosuppressed mice, but the peak parasitemia was 16-fold lower than that of the wild type. Differentiation of the proliferating long slender to the nonproliferating short stumpy bloodstream form is triggered by an autocrine factor, stumpy induction factor (SIF). The knockout differentiated prematurely in mice and in culture, suggestive of increased sensitivity to SIF. In contrast, a null mutant of a cell line refractory to SIF was able to proliferate normally. The differentiation phenotype was partially rescued by complementation with wild-type TbMAPK5 but exacerbated by introduction of a nonactivatable mutant form. Our results indicate a regulatory function for TbMAPK5 in the differentiation of bloodstream forms of T. brucei that might be exploitable as a target for chemotherapy against human sleeping sickness.

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* Corresponding author. Mailing address: Institut für Pathologie, Universität Bern, Murtenstrasse 31, CH-3010 Bern, Switzerland. Phone: 41-31-632 99 43. Fax: 41-31-381 87 64. E-mail: erik.vassella{at}pathology.unibe.ch.

G.B. and S.M. contributed equally to this work.

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Eukaryotic Cell, July 2006, p. 1126-1135, Vol. 5, No. 7
1535-9778/06/$08.00+0     doi:10.1128/EC.00094-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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