The Semaphorin receptor PlexinA3 mediates neuronal apoptosis during dorsal root ganglia development.
Extensive neuronal cell death during development is believed to be due to a limiting supply of neurotrophic factors. In vitro studies suggest that axon guidance molecules directly regulate neuronal survival, raising the possibility that they play a direct role in neuronal cell death in vivo. However, guidance errors may also influence survival indirectly due to loss of target-derived neurotrophic support. The role of guidance molecules in neuronal death in vivo has thus been difficult to decipher. Semaphorin3A, a repulsive guidance cue for sensory neurons, can induce sensory neuron death in vitro. Null mice studies of the Semaphorin3A coreceptors showed that guidance activity is mediated by PlexinA4, but PlexinA3 partially compensates in PlexinA4(-/-) mice. Here we demonstrate that both Plexins contribute to Sema3A-induced cell death in vitro, albeit in a different hierarchy. PlexinA3 is absolutely required, while PlexinA4 makes a smaller contribution to cell death. We found that PlexinA3(-/-) mice, which, unlike PlexinA4(-/-) mice, do not exhibit sensory axon patterning defects, show reduced neuronal apoptosis and an increased number of DRG neurons. Semaphorin3A involvement in neuronal death in vivo was demonstrated by a sensitization experiment using the proapoptotic effector Bax. Our results identify Plexins as mediators of Semaphorin-induced cell death in vitro, and provide the first evidence implicating Semaphorin/Plexin signaling in neuronal survival independent of its role in axon guidance. The results also support the idea that naturally occurring neuronal cell death reflects not only competition for target-derived trophic factors, but also the action of proapoptotic signaling via a Semaphorin/Plexin pathway.
Ben-Zvi
Ayal
A
The Hubert H. Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel.
Manor
Osnat
O
Schachner
Melitta
M
Yaron
Avraham
A
Tessier-Lavigne
Marc
M
Behar
Oded
O
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology* / Q000196:embryology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D060850:LIM-Homeodomain Proteins; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000502:physiology*; D040121:Semaphorin-3A / Q000494:pharmacology; D039961:Semaphorins / Q000235:genetics; D018709:Statistics, Nonparametric; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection / Q000379:methods; D051028:bcl-2-Associated X Protein / Q000172:deficiency
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; C492112:Plxna3 protein, mouse; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; D039961:Semaphorins; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; C063843:insulin gene enhancer binding protein Isl-1; D020932:Nerve Growth Factor; D053148:Caspase 3