Borna disease virus persistent infection activates mitogen-activated protein kinase and blocks neuronal differentiation of PC12 cells.
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.
Hans
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A
Unité des Virus Lents, CNRS URA 1930, Institut Pasteur, 75724 Paris Cedex 15, France.
Syan
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S
Crosio
C
C
Sassone-Corsi
P
P
Brahic
M
M
Gonzalez-Dunia
D
D
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001890:Borna Disease / Q000378:metabolism*; D001891:Borna disease virus / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D019922:GAP-43 Protein / Q000096:biosynthesis; D007700:Kinetics; D020935:MAP Kinase Signaling System; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D016708:Synaptophysin / Q000096:biosynthesis / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D019922:GAP-43 Protein; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D016708:Synaptophysin; D014446:Tyrosine 3-Monooxygenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases