c-jun is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation.

Palmada M, Kanwal S, Rutkoski NJ, Gustafson-Brown C, Johnson RS, Wisdom R, Carter BD, Gufstafson-Brown C
J Cell Biol. 2002 158 (3): 453-61

PMID: 12163468 · PMCID: PMC2173823 · DOI:10.1083/jcb.200112129

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.

MeSH Terms (24)

Animals Apoptosis Base Sequence Brain-Derived Neurotrophic Factor Cells, Cultured Cycloheximide Gene Expression Regulation, Developmental Genetic Vectors Green Fluorescent Proteins Immunohistochemistry Indicators and Reagents Integrases Luminescent Proteins Mice Mice, Knockout Mutation Nerve Growth Factor Neurons Protein Synthesis Inhibitors Proto-Oncogene Proteins c-jun Receptor, Nerve Growth Factor Superior Cervical Ganglion Transfection Viral Proteins

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