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Originally published In Press as doi:10.1074/jbc.M005107200 on November 9, 2000

J. Biol. Chem., Vol. 276, Issue 10, 7258-7265, March 9, 2001
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Borna Disease Virus Persistent Infection Activates Mitogen-activated Protein Kinase and Blocks Neuronal Differentiation of PC12 Cells*

Aymeric HansDagger §, Sylvie SyanDagger , Claudia Crosio, Paolo Sassone-Corsi, Michel BrahicDagger , and Daniel Gonzalez-DuniaDagger ||

From the Dagger  Unité des Virus Lents, CNRS URA 1930, Institut Pasteur, 75724 Paris Cedex 15 and the  Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM, 67404 Illkirch, Strasbourg, France

Persistence of Borna disease virus (BDV) in the central nervous system causes damage to specific neuronal populations. BDV is noncytopathic, and the mechanisms underlying neuronal pathology are not well understood. One hypothesis is that infection affects the response of neurons to factors that are crucial for their proliferation, differentiation, or survival. To test this hypothesis, we analyzed the response of PC12 cells persistently infected with BDV to the neurotrophin nerve growth factor (NGF). PC12 is a neural crest-derived cell line that exhibits features of neuronal differentiation in response to NGF. We report that persistence of BDV led to a progressive change of phenotype of PC12 cells and blocked neurite outgrowth in response to NGF. Infection down-regulated the expression of synaptophysin and growth-associated protein-43, two molecules involved in neuronal plasticity, as well as the expression of the chromaffin-specific gene tyrosine hydroxylase. We showed that the block in response to NGF was due in part to the down-regulation of NGF receptors. Moreover, although BDV caused constitutive activation of the ERK1/2 pathway, activated ERKs were not translocated to the nucleus efficiently. These observations may account for the absence of neuronal differentiation of persistently infected PC12 cells treated with NGF.

* This work was supported by the Institut Pasteur, the Centre National de la Recherche Scientifique and by a grant from the Ministère de l'Education Nationale, de la Recherche et de la Technologie (Programme de Recherche Fondamentale en Microbiologie et Maladies Infectieuses et Parasitaires).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a doctoral fellowship from the Ministère de l'Education Nationale et de l'Enseignement Supérieur.

|| To whom correspondence should be addressed: Unité des Virus Lents, Institut Pasteur, 28, rue du Dr Roux, 75724 Paris Cedex 15, France. E-mail: ddune@ pasteur.fr.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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