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Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75
P Casaccia-Bonnefil1, B D Carter, R T Dobrowsky
1Department of Cell Biology and Anatomy, Hematology/Oncology Division, Cornell University Medical College, New York 10021, USA.
Abstract:
Members of the nerve growth factor (NGF) family promote the survival of neurons during development. NGF specifically activates the receptor trkA, initiating a signal transduction cascade which ultimately blocks cell death. Here we show that NGF can have the opposite effect, inducing the death of mature oligodendrocytes cultured from postnatal rat cerebral cortex. This effect was highly specific, because NGF had no effect on oligodendrocyte precursors and astrocytes. Other neurotrophins such as brain-derived neurotrophin factor (BDNF) and neurotrophin-3 (NT-3) did not induce cell death. NGF binding to mature oligodendrocytes expressing the p75 neurotrophin receptor, but not trkA, resulted in a sustained increase of intracellular ceramide and c-Jun amino-terminal kinase (JNK) activity, which are thought to participate in a signal transduction pathway leading to cell death. Taken together, these results indicate that NGF has the ability to promote cell death in specific cell types through a ligand-dependent signalling mechanism involving the p75 neurotrophin receptor.
Insights
Nerve growth factor (NGF) typically supports neuron survival. However, this study reveals NGF induces mature oligodendrocyte death via the p75 receptor, not trkA, highlighting a novel cell death pathway.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Signaling
Background:
- Nerve growth factor (NGF) family members are crucial for neuronal survival during development.
- NGF signaling through the trkA receptor typically initiates pro-survival cascades.
- The role of NGF in mature oligodendrocytes and its specific receptor interactions were not fully understood.
Purpose of the Study:
- To investigate the effect of NGF on mature oligodendrocytes.
- To determine the specific receptor and signaling pathway involved in NGF-induced oligodendrocyte death.
- To differentiate NGF's role in mature oligodendrocytes versus precursor cells.
Main Methods:
- Cultured mature oligodendrocytes, oligodendrocyte precursors, and astrocytes from postnatal rat cerebral cortex.
- Treated cells with NGF, BDNF, and NT-3.
- Assessed cell death, receptor expression (trkA, p75), intracellular ceramide levels, and c-Jun amino-terminal kinase (JNK) activity.
Main Results:
- NGF induced significant death in mature oligodendrocytes but had no effect on precursors or astrocytes.
- NGF binding to mature oligodendrocytes occurred via the p75 neurotrophin receptor, not trkA.
- NGF triggered sustained increases in intracellular ceramide and JNK activity, indicative of a cell death pathway.
Conclusions:
- NGF can induce cell death in specific mature cell types, opposing its known neurotrophic role.
- The p75 neurotrophin receptor mediates NGF-induced oligodendrocyte death.
- This pathway involves increased ceramide and JNK activity, revealing a novel mechanism for programmed cell death.