Semaphorins as mediators of neuronal apoptosis

Shrinkage and collapse of the neuritic network are often observed during th e process of neuronal apoptosis, However, the molecular and biochemical bas is for the axonal damage associated with neuronal cell death is still uncle ar. We present evidence for the involvement of axon guidance molecules with repulsive cues in neuronal cell death. Using the differential display appr oach, an up-regulation of collapsin response mediator protein was detected in sympathetic neurons undergoing dopamine-induced apoptosis, A synchronize d induction of mRNA of the secreted collapsin-1 and the intracellular colla psin response mediator protein that preceded commitment of neurons to apopt osis was detected, Antibodies directed against a conserved collapsin-derive d peptide provided marked and prolonged protection of several neuronal cell types from dopamine-induced apoptosis, Moreover, neuronal apoptosis was in hibited by antibodies against neuropilin-1, a putative component of the sem aphorin III/ collapsin-1 receptor. Induction of neuronal apoptosis was also caused by exposure of neurons to semaphorin Ill-alkaline phosphatase secre ted from 293EBNA cells. Anti-collapsin-1 antibodies were effective in block ing the semaphorin Ill-induced death process. We therefore suggest that, be fore their death, apoptosis-destined neurons may produce and secrete destru ctive axon guidance molecules that can affect their neighboring cells and t hus transfer a "death signal" across specific and susceptible neuronal popu lations.