title: c-jun is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation.
abstract: Sympathetic neurons depend on NGF binding to TrkA for their survival during vertebrate development. NGF deprivation initiates a transcription-dependent apoptotic response, which is suggested to require activation of the transcription factor c-Jun. Similarly, apoptosis can also be induced by selective activation of the p75 neurotrophin receptor. The transcriptional dependency of p75-mediated cell death has not been determined; however, c-Jun NH2-terminal kinase has been implicated as an essential component. Because the c-jun-null mutation is early embryonic lethal, thereby hindering a genetic analysis, we used the Cre-lox system to conditionally delete this gene. Sympathetic neurons isolated from postnatal day 1 c-jun-floxed mice were infected with an adenovirus expressing Cre recombinase or GFP and analyzed for their dependence on NGF for survival. Cre immunopositive neurons survived NGF withdrawal, whereas those expressing GFP or those uninfected underwent apoptosis within 48 h, as determined by DAPI staining. In contrast, brain-derived neurotrophic factor (BDNF) binding to p75 resulted in an equivalent level of apoptosis in neurons expressing Cre, GFP, and uninfected cells. Nevertheless, cycloheximide treatment prevented BDNF-mediated apoptosis. These results indicate that whereas c-jun is required for apoptosis in sympathetic neurons on NGF withdrawal, an alternate signaling pathway must be induced on p75 activation.
authors.affiliation: Department of Biology, University of California, San Diego, 92138, USA.
authors.forename: M
authors.initials: M
authors.lastname: Palmada
authors.forename: S
authors.initials: S
authors.lastname: Kanwal
authors.forename: N J
authors.initials: NJ
authors.lastname: Rutkoski
authors.forename: C
authors.initials: C
authors.lastname: Gustafson-Brown
authors.forename: R S
authors.initials: RS
authors.lastname: Johnson
authors.forename: R
authors.initials: R
authors.lastname: Wisdom
authors.forename: B D
authors.initials: BD
authors.lastname: Carter
authors.forename: C
authors.initials: C
authors.lastname: Gufstafson-Brown
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D019426:Integrases / Q000235:genetics; D008164:Luminescent Proteins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000187:drug effects / Q000502:physiology; D020932:Nerve Growth Factor / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency* / Q000235:genetics; D020800:Receptor, Nerve Growth Factor / Q000187:drug effects / Q000378:metabolism*; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007202:Indicators and Reagents; D008164:Luminescent Proteins; D011500:Protein Synthesis Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D020800:Receptor, Nerve Growth Factor; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; D020932:Nerve Growth Factor; D003513:Cycloheximide; C045073:Cre recombinase; D019426:Integrases