Autocrine regulation of apoptosis and bcl-2 expression by nerve growth factor in early differentiating cerebellar granule neurons involves low affinity neurotrophin receptor.

摘要

Cerebellar granule neurons produce homogenous cultures that provide a unique opportunity for quantifying the apoptosis by propidium iodide- and deoxynucleotidyl transferase-flow cytometry combined analysis and for studying its regulation by neurotrophins. Nerve growth factor (NGF) was found to promote postmitotic survival by preventing apoptosis of newly formed and early differentiated granule neurons. This regulation could be through protein bcl-2, which was underexpressed in apoptotic granule neurons and up-regulated by NGF in a dose-dependent manner. Antibodies against low affinity NGF receptors (p75NTR) mimicked the effects of NGF, suggesting that this receptor, which is transiently expressed at high levels in postmitotic granule neurons, is involved in apoptosis signaling. Since these neurons constitutively produce NGF, this is the first demonstration of an autocrine regulation of apoptosis in the CNS. Preliminary results strongly suggest that neurotrophin-3 (NT-3) and brain derived neurotrophic factor (BDNF) are also involved in the regulation of cell death, by first promoting necrosis and then protecting the remaining cells from apoptosis. In contrast, NGF may protect against two forms of cell death and act preferentially at early stages of granule neuron development. The possibility that these neurotrophins may act in parallel and/or in sequence to regulate survival of developing granule neurons through different mechanisms is discussed in the light of findings on neurotrophin and p75NTR patterns, and p75NTR/high affinity Trk receptor coexpression.