Specific pathophysiological functions of JNK isoforms in the brain.
We have investigated the effect of JNK1 ko, JNK2 ko, JNK3 ko, JNK2+3 ko and c-JunAA mutation on neuronal survival in adult transgenic mice following ischemia, 6-hydroxydopamine induced neurotoxicity, axon transection and kainic acid induced excitotoxicity. Deletion of JNK isoforms indicated the compartment-specific expression of JNK isoforms with 46-kDa JNK1 as the main phosphorylated JNK isoform. Permanent occlusion of the MCA significantly enlarged the infarct area in JNK1 ko, which showed an increased expression of JNK3 in the penumbra. Survival of dopaminergic neurons in the substantia nigra compacta (SNC) following intrastriatal injection of 6-hydroxydopamine was transiently improved in JNK3 ko and c-JunAA mice after 7 days, but not 60 days. Following transection of the medial forebrain bundle, however, JNK3 ko conferred persisting neuroprotection of axotomised SNC neurons. None of the JNK ko and c-JunAA mutation affected the survival of facial motoneurons following peripheral axotomy when investigated after 90 days. Finally, we determined the impact of JNK ko on the survival of animals and the degeneration of hippocampal neurons following kainic acid. JNK3 ko mice were substantially resistant against and survived kainic acid-induced seizures. JNK3 ko and JNK1 ko showed a nonsignificant tendency for decreased or increased death of hippocampal neurons, respectively. Surprisingly, the deletion of a single JNK isoform did not attenuate the immunocytochemical signal of phosphorylated c-Jun irrespective on the experimental set-up. This comprehensive study provides novel insights into the context-dependent physiological and pathological functions of JNK isoforms.
Brecht
Stephan
S
Institute of Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Hospitalstrasse 4, 24105 Kiel, Germany.
Kirchhof
Rainer
R
Chromik
Ansgar
A
Willesen
Mette
M
Nicolaus
Thomas
T
Raivich
Gennadij
G
Wessig
Jan
J
Waetzig
Vicki
V
Goetz
Mario
M
Claussen
Malte
M
Pearse
Damien
D
Kuan
Chia-Yi
CY
Vaudano
Elisabetha
E
Behrens
Axel
A
Wagner
Erwin
E
Flavell
Richard A
RA
Davis
Roger J
RJ
Herdegen
Thomas
T
D000818:Animals; D017763:Autonomic Denervation / Q000379:methods; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation; D005155:Facial Nerve Diseases / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D007608:Kainic Acid; D008297:Male; D008474:Medial Forebrain Bundle / Q000293:injuries / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D016627:Oxidopamine; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology*; D012694:Serine / Q000276:immunology; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D007527:Isoenzymes; D016755:Proto-Oncogene Proteins c-jun; D012694:Serine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D007608:Kainic Acid