Leukemia inhibitory factor requires concurrent p75(LNTR) signaling to induce apoptosis of cultured sympathetic neurons

Sean I. Savitz, John A. Kessler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Apoptosis may result either from positive induction by ligand binding to a plasma membrane receptor or from negative induction attributable to loss of a suppressor signal. For example, apoptosis of developing sympathetic neurons may be induced in culture either by exposure to leukemia inhibitory factor (LIF) or by deprivation of nerve growth factor. This study compared the cell death pathways activated in sympathetic neurons by these two different stimuli. Both types of cell death were developmentally regulated; both were maximal in the immediate postnatal period and disappeared over the next 2 weeks. Both types of cell death were reduced by genetic deletion of Bax or by virally mediated overexpression of Bcl-2. Similarly both were reduced by inhibition of caspase activity or by inhibition of Nedd-2 synthesis with antisense oligonucleotides. Finally, both involved activation of c-Jun N- terminal kinase (JNK) signaling. Nedd-2 expression by sympathetic neurons declined in parallel with the developmental loss of LIF-mediated cell death, suggesting that downregulation of the caspase during development may underlie the loss of cytokine-mediated apoptosis. Treatment of sympathetic neurons with an antibody that blocks the function of the low-affinity neurotrophin receptor (p75(LNTR)) prevented LIF-induced cell death. Similarly genetic deletion of p75(LNTR) prevented apoptosis after LIF treatment. These observations suggest that concurrent p75(LNTR) signaling is necessary for LIF-induced cell death and that cytokine-mediated cell death and growth factor deprivation appear to activate the same intracellular pathways involving JNK signaling.

Original languageEnglish (US)
Pages (from-to)4198-4205
Number of pages8
JournalJournal of Neuroscience
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2000

Keywords

  • Apoptosis
  • C-JUN N-terminal kinase
  • Gp130
  • Leukemia inhibitory factor
  • P75
  • Sympathetic neuron

ASJC Scopus subject areas

  • Neuroscience(all)

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