Neurotrophins in cell survival/death decisions.

Abstract

Neurotrophins are target-derived soluble factors required for neuronal survival. Nerve growth factor (NGF) the founding member of the neurotrophin family, binds to two types of receptors: Trk tyrosine kinase and the p75 neurotrophin receptor, which belongs to the Fas-tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to Trk receptor tyrosine kinases initiate signaling cascades that promote cell survival sand differentiation. In contrast, p75 NGFR has been shown to modulate the susceptibility to death of selective cellular populations--including differentiated rat oligodendrocytes--in specific conditions. Notably, NGF effect on viability was only observed in fully differentiated oligodendrocytes and not in oligodendrocyte progenitor cells. The effect of p75 activation on oligodendrocyte survival correlates with increased activity of the stress related kinase JNK-1 and cleavage of specific caspases. Indeed, activation of additional stress pathways or impairment of survival signals may be required for p75 mediated activation of cell death execution programs. Interestingly, co-expression of the TrkA receptor in the same cell type abolishes the JNK-1 mediated death signal and induces MAP kinase activity, resulting in cell survival. This suggests that glial cell survival results from a balance between positive and negative regulators modulated by selective signalling pathways by tyrosine kinases and cytokine receptors.