Semaphorins as mediators of neuronal apoptosis.
Shrinkage and collapse of the neuritic network are often observed during the process of neuronal apoptosis. However, the molecular and biochemical basis for the axonal damage associated with neuronal cell death is still unclear. We present evidence for the involvement of axon guidance molecules with repulsive cues in neuronal cell death. Using the differential display approach, an up-regulation of collapsin response mediator protein was detected in sympathetic neurons undergoing dopamine-induced apoptosis. A synchronized induction of mRNA of the secreted collapsin-1 and the intracellular collapsin response mediator protein that preceded commitment of neurons to apoptosis was detected. Antibodies directed against a conserved collapsin-derived peptide provided marked and prolonged protection of several neuronal cell types from dopamine-induced apoptosis. Moreover, neuronal apoptosis was inhibited by antibodies against neuropilin-1, a putative component of the semaphorin III/collapsin-1 receptor. Induction of neuronal apoptosis was also caused by exposure of neurons to semaphorin III-alkaline phosphatase secreted from 293EBNA cells. Anti-collapsin-1 antibodies were effective in blocking the semaphorin III-induced death process. We therefore suggest that, before their death, apoptosis-destined neurons may produce and secrete destructive axon guidance molecules that can affect their neighboring cells and thus transfer a "death signal" across specific and susceptible neuronal populations.
Shirvan
A
A
Department of Neurology and Felsenstein Medical Research Center, Rabin Medical Center, Petach Tiqva, Israel.
Ziv
I
I
Fleminger
G
G
Shina
R
R
He
Z
Z
Brudo
I
I
Melamed
E
E
Barzilai
A
A
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D002642:Chick Embryo; D004298:Dopamine / Q000494:pharmacology / Q000502:physiology; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D039942:Neuropilin-1; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040121:Semaphorin-3A; D015854:Up-Regulation
D000906:Antibodies; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; C095114:collapsin response mediator protein-2; D039942:Neuropilin-1; D004298:Dopamine